Di-substituted pyrazole compounds for the treatment of diseases

ABSTRACT

Provided herein are compounds, pharmaceutical compositions comprising the compounds, and methods of using the compounds and compositions in treating a condition, disease, or disorder associated with abnormal activation of the SREBP pathway, including metabolic disorders such as obesity, cancer, cardiovascular disease, and nonalcoholic fatty liver disease (NAFLD) wherein the compound is according to Formula (I).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 16/097,211, filedOct. 26, 2018, which is a 371 of International Application No.PCT/US2017/030261 filed Apr. 28, 2017, which claims benefit of U.S.Provisional Patent Application No. 62/330,049 filed Apr. 29, 2016. Thecontents of which applications are hereby incorporated by referenceherein in their entireties.

STATEMENT OF GOVERNMENT RIGHTS

This invention was made with Government support under contract5R44HL112484-2 awarded by the National Institutes of Health. TheGovernment has certain rights in this invention.

FIELD

Provided herein are compounds, pharmaceutical compositions comprisingthe compounds, and methods of using the compounds and compositions intreating a condition, disease, or disorder associated with abnormalactivation of the SREBP pathway, including metabolic disorders such asobesity, cancer, cardiovascular disease, and nonalcoholic fatty liverdisease (NAFLD).

BACKGROUND

Metabolic syndrome comprises many cardiovascular risk factors that,occurring together, increase a person's risk of diseases like heartdisease, stroke, and type 2 diabetes. These risk factors includehypertension, dyslipidemia, obesity, high blood sugar, pancreatic β-celldysfunction, and atherosclerosis. In addition, increasing evidence showa strong link between metabolic syndrome and a variety of cancersincluding, breast, liver, and prostate (Gabitova et al. Clin Cancer Res.2014, 20(1), 28). Disturbing the balance between energy expenditure andfood intake, in addition to predisposing genetic factors, can result inpathological conditions, diseases, or disorders such as obesity,diabetes, and cardiovascular disease. Targeting metabolic pathways,especially those that are related to lipid and fat metabolism, has beenused to develop drugs against these diseases (Padwal et al. Lancet 2007,369(9555), 71). Although pharmacological intervention against individualabnormalities associated with metabolic syndrome is possible, it wouldbe of great advantage to target multiple metabolic pathways by loweringlipids (triglycerides and cholesterol), in addition to controlling bloodglucose in diabetic patients.

One of the major consequences of metabolic syndrome and obesity inparticular is the development of NAFLD. NAFLD is a condition that iscaused by excess of fat accumulation in the liver of patients without ahistory of alcohol abuse. NAFLD is the liver manifestation of metabolicsyndrome and has been increasing worldwide in line with the epidemicincrease in obesity, type 2 diabetes, and dyslipidemia (Takahashi Y,Fukusato T. Histopathology of nonalcoholic fatty liverdisease/nonalcoholic steatohepatitis. World J Gastroenterol. 2014 Nov.14; 20(42):15539-48). NAFLD can be a simple steatosis (triglycerideaccumulation in liver) due to shift in de novo fatty acid metabolism tonet lipogenesis from lipolysis, or the more serious nonalcoholicsteatohepatitis (NASH). NASH is considered the major chronic liverdisease, with serious damage to liver such as interlobular inflammation,hepatocellular ballooning and fibrosis and it may lead to livercirrhosis and hepatocellular carcinoma (Schreuder et al. World JGastroenterol 2008, 14(16), 2474). It is estimated that 15% of the adultpopulation in the US have NAFLD and about 3-4% suffer from NASH (Ekstedtet al. Hepatology 2006, 44(4), 865). Currently treatment for NASH islimited to substantial weight loss by methods such as bariatric surgery,insulin sensitizing agents and Vitamin E supplements, in addition tolife style modification by diet and exercise.

Another risk factor associated with metabolic syndrome is thedevelopment of diabetes mellitus where dyslipidemia, including highlevels of LDL cholesterol, is very common in these patients. Thesepatients are at very high risk of developing atheroscleroticcardiovascular disease. Numerous studies including genetic studiessupport the notion that high levels of LDL are casually implicated incoronary artery disease and that lowering LDL cholesterol reduces therisk of cardiovascular events (Ajufo et al. Lancet Diabetes Endocrinol.2016 May; 4(5):436-46). At the genetic level, familialhypercholesterolemia, a mendelian disorder caused by mutations in LDLReceptor (LDLR) and other genes in LDL-Receptor pathways is associatedwith high levels of LDL and increased risk of cardiovascular disease(Kolansky et al. Am J Cardiol. 2008 Dec. 1; 102(11):1438-43). One of theknown genes that was linked to familial hypercholesterolemia is theproprotein convertase subtilisin/kexin type 9 (PCSK 9) which is secretedby hepatocytes (Urban et al. J. Am. Coll. Cardiol. 2013 Oct. 15;62(16):1401-8). It was shown that gain of function in PCSK 9 caused highlevel of LDL and increased cardiovascular events (Abifadel M et al. NatGenet. 2003 June; 34(2):154-6). On the other hand patients withmutations in this gene had very low level of LDL suggesting that PCSK9is potential therapeutic target for reducing LDL cholesterol (Cohen etal. Nat Genet. 2005 February; 37(2):161-5).

Animals, including humans, rely on fat and carbohydrate as their majorenergy sources required to sustain their activity needs. A diet varyingin fat or carbohydrate contents contributes to energy metabolism ofanimals including humans. Long chain fatty acids are major sources ofenergy and important components of the lipids that comprise the cellularmembranes. They are derived from food and synthesized de novo fromacetyl-CoA. Hence, acetyl-CoA is an intermediate that interrelatesglucose and fatty acid metabolism, and is converted to malonyl-CoA bythe rate limiting enzyme acetyl-CoA carboxylase (ACC). The synthesis offatty acids by fatty acid synthase (FAS) requires acetyl-CoA,malonyl-CoA, and NADPH. Malonyl-CoA is the C₂ donor in the de novosynthesis of long-chain fatty acids (C₁₄-C₁₈) and very long chain fattyacids (C₂₀-C₂₆).

Cholesterol is derived from food and synthesized from acetyl-CoA. Theconversion of carbohydrates into acyl glycerides through de novo fattyacid and cholesterol synthesis involves at least 12 and 23 enzymaticreactions, respectively. Expression levels of the genes encoding theseenzymes are controlled by three transcription factors, designated sterolregulatory element-binding proteins (SREBPs), SREBP-1a, -1c, andSREBP-2. SREBPs are membrane-bound proteins and are members of a classof the basic helix-loop-helix leucin zipper family of transcriptionfactors. Unlike other leucin zipper members of transcription factors,SREBPs are synthesized as ER-membrane-bound precursors, which need to beproteolytically released by two proteases bound to the Golgi membrane,Site-1 and Site-2 proteases, to generate active forms, nSREBPs, thatactivate transcription of target genes in the nucleus (DeBose-Boyd etal. Cell 1999, 99 (7), 703; Sakai et al. Cell 1996, 85, 1037). Theproteolytic activation of SREBPs is tightly regulated by sterols thatare known to induce the interaction of the SREBP cleavage-activatingprotein (SCAP) with the ER membrane-bound insulin-induced gene (INSIG),thereby inhibiting the exit of the SREBP/SCAP complex from the ER (Yabeet al. Proc Natl Acad Sci USA 2002, 99(20), 12753; Yang et al., Cell2002, 110, 489-500). When sterols accumulate in the ER membranes, theSCAP/SREBP complex fails to exit the ER to the Golgi apparatus, and theproteolytic processing of SREBPs is suppressed. Thus, SREBPs are keylipogenic transcription factors that govern the homeostasis of fatmetabolism. Interestingly, SREBP isoforms-1a and -1c have some overlapin target genes, yet they have distinct roles in lipid metabolism(Eberle et al. Biochimie 2004, 86 (11), 839).

Recently, numerous studies have shown that SREBPs integrate several cellsignals to regulate lipogenesis and other pathways important fordiseases such as type II diabetes, dyslipidemia, cancer and the immuneresponse (Shao W and Espenshade P J. Cell Metab. 2012, 16, 414). Inaddition, studies in animal models and humans suggested a strongcorrelation between upregulation of SREBPs and SREBP-1c in particularand the pathogenesis of these diseases and reducing the activity ofSREBPs may be beneficial to treat these diseases and ameliorate theircomplications (Zhao et al. Diabetes 2014, (63) 2464). In addition tolife style treatment, individual drugs have been developed to treatthese diseases that associated with the metabolic syndrome. The centralrole of SREBPs in the regulation of lipids and their potential role as amajor player in several diseases raised the possibility of novelapproaches to treat several risk factors with one drug (Soyal et al.Trends Pharmacol Sciences 2015, 36, 406).

Recently, several studies have provided proof of concept for theefficacy of small molecules targeting transcriptional SREBPs activity totreat several components of metabolic syndrome. Betulin, a pentacyclictriterpene that naturally occurs in birch bark, decreased the level ofthe mature active form of both SREBP-1 and 2 in a human liver Huh-7 cellline, resulting in down regulation of genes involved in cholesterol andfatty acid synthesis (Tang et al. Cell Metabol. 2011, 13, 44). Theseauthors presented evidence showing that betulin directly interacts withSCAP. Mice that were fed western diet, which induces obesity, fattyliver and dyslipidemia, and treated with betulin had lower weight gain,and accumulated less fat without affecting food intake (Tang et al. CellMetabol. 2011, 13, 44). In addition, the treated mice had lowertriglycerides, cholesterol plasma glucose and improved insulinsensitivity. These metabolic improvements were reflected in reducedlevels of hepatic SREBP and its target genes.

Major hallmarks of tumor cells are over expression and increasedmetabolic activities such as glucose consumption, protein and nucleicacid synthesis and increased de novo fatty acid synthesis (Menendez, J.A., and Lupu, R. Nat. Rev. Cancer 2007, 7, 763). It has been shown that,contrary to normal cells, various tumor cells are very active in de novofatty acid biosynthesis, irrespective of the extracellular lipids, andthat de novo fatty acids accounted for all fatty acid esterification inthe tumor cells (Medes et al. Cancer Research 1953, 13, 27.)Pharmacological and RNAi knockdown approaches against ACC and FAS havebeen reported (Brusselmans et al. Cancer Research 2005, 65, 6719-6725;Kuhajda et al. Proceedings of the National Academy of Sciences of theUnited States of America 2000, 97, 3450-3454; Menendez, et al. Int JCancer 2005, 115, 19-35). These studies showed, that inhibiting theseenzymes, induced growth inhibition and an apoptotic effect againstbreast and prostate cancer cells. In this regard, SREBP-1 and 2 asmaster regulators of lipid biosynthesis play a major role in tumorgrowth. In support of the role of SREBP in cancer, several studies haveshown that inhibition of SREBP activation using RNAi and a smallmolecule resulted in significant growth inhibition. On the other hand itwas recently reported that glucose-mediated N-glycolsylation of SCAPresulted in its stabilization and activation of SREBP-1 to promote tumorgrowth in glioblastoma (Cheng et al. 2015). These findings suggest thattargeting the SCAP/SREBP complex is a promising approach for treatingcancer and metabolic diseases.

Fatostatin is a diarylthiazole small molecule and is the firstnon-cholesterol molecule that acts on the translocation of SREBPs fromthe ER to the Golgi, hence affecting the downregulation of the majorplayers in lipid metabolism, including triglyceride (TG) and cholesterol(Kamisuki et al. Chem. Biol. 2009, 16, 882-92; Kamisuki et al. J. Med.Chem. 2011 54, 4923). Fatostatin derivatives such as FGH10019 bindspecifically to SCAP at a distinct site from the sterol-binding domain.As a result of FGH10019 action, SREBPs are retained in the ER, blockingtheir transportation to the Golgi apparatus, where they are processed byproteases to produce the nuclear active form bHLH. Recently severalstudies showed that fatostatin derivatives inhibited cell growth incells and animal models for breast and prostate cancer, thus isvalidating the potential use of these compounds to treat cancer (Li etal. Mol. Cancer. Ther. 2014, 13(4), 855; Li et al. Oncotarget. 2015,6(38), 41018).

However, while fatostatin could provide an important starting point forproviding small molecules for new pharmacological interventions tocombat metabolic diseases, it has liabilities which may preclude its useas a drug. Thus, small molecules with improved drug-like qualities areneeded.

SUMMARY OF THE INVENTION

Provided herein are compounds, pharmaceutical compositions comprisingthe compounds, and methods of using the compounds and compositions intreating a condition, disease, or disorder associated with abnormalactivation of the SREBP pathway, including metabolic disorders such asobesity, cancer, cardiovascular disease, and NAFLD.

In one aspect, provided is a Compound of Formula (I):

where

-   R¹ is phenyl, pyridinonyl, pyridinyl, pyrimidinyl, pyridazinyl, or    pyrazinyl; where the phenyl, pyridinyl, pyrimidinyl, pyridazinyl,    and pyrazinyl rings are optionally substituted with 1, 2, or 3    R^(1a) and where the pyridinonyl is substituted on the nitrogen with    R^(1b) and is additionally optionally substituted with 1, 2, or 3    Ria;-   each R^(1a) is independently halo, alkyl, alkenyl, haloalkyl,    cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or    heterocycloalkylalkyl;-   R^(1b) is hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl,    cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl;-   R² is

where 0, 1, or 2 of X¹-X⁴ are nitrogen and the remaining are carbon;

-   R^(2a) is —NR^(5a)S(O)₂R^(5b) or —NR^(6a)R^(6b);-   each R^(2b) is independently halo, alkyl, haloalkyl, —NO₂, or cyano;-   R³ is hydrogen, halo, alkyl, or haloalkyl;-   R⁴ is hydrogen, halo, alkyl, or haloalkyl;-   R^(5a) and R^(6a) are independently hydrogen or alkyl; and-   R^(5b) and R^(6b) are independently alkyl; haloalkyl; cycloalkyl;    cycloalkylalkyl; heterocycloalkyl; heterocycloalkylalkyl; and-   wherein each cycloalkyl, either alone or as part of another group,    is independently optionally substituted with one or two groups    independently selected from the group consisting of alkyl, halo, and    haloalkyl; or-   a pharmaceutically acceptable salt thereof,-   provided that the compound is not    N-methyl-6-(1-phenyl-1H-pyrazol-4-yl)pyridazin-3-amine;    N-ethyl-6-(1-phenyl-1H-pyrazol-4-yl)pyridazin-3-amine; or    N-propyl-6-(1-phenyl-1H-pyrazol-4-yl)pyridazin-3-amine.

In another aspect, provided is a Compound according to Formula (II)

where

-   R¹ is phenyl, pyridinonyl, pyridinyl, pyrimidinyl, pyridazinyl, or    pyrazinyl; where the R¹ phenyl, pyridinyl, pyrimidinyl, pyridazinyl,    and pyrazinyl rings are substituted with one R^(1a) and additionally    optionally substituted with a second R^(1a) and additionally    optionally substituted with a third R^(1a), and where the    pyridinonyl is substituted on the nitrogen with R^(1b) and is    additionally optionally substituted with 1, 2, or 3 R^(1a);-   each R^(1a) is independently halo, alkyl, alkenyl, haloalkyl,    cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or    heterocycloalkylalkyl;-   R^(1b) is hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl,    cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl;-   R²⁰ is

where 0, 1, or 2 of X¹-X⁴ are nitrogen and the remaining are carbon;each R^(2b) is independently halo, alkyl, haloalkyl, —NO₂, or cyano;

-   R^(2c) is —NO₂ or NH₂;-   R³ is hydrogen or alkyl;-   R⁴ is hydrogen or alkyl;-   R^(5a) and R^(6a) are independently hydrogen or alkyl; and-   R^(5b) and R^(6b) are independently alkyl, haloalkyl, cycloalkyl,    cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl; and-   wherein each cycloalkyl, either alone or as part of another group,    is independently optionally substituted with one or two groups    independently selected from the group consisting of alkyl, halo, and    haloalkyl; or-   a pharmaceutically acceptable salt thereof,-   provided that the compound is not    4-(1-(3-methylpyridin-4-yl)-1H-pyrazol-4-yl)aniline;    4-(1-(2-methylpyridin-4-yl)-1H-pyrazol-4-yl)aniline; or    4-(1-(3-chloropyridin-4-yl)-1H-pyrazol-4-yl)aniline.

In another aspect, provided is a Compound according to Formula (III)

where

-   PG¹ is a nitrogen protecting group;-   R² is

where 0, 1, or 2 of X¹-X⁴ are nitrogen and the remaining are carbon;R^(2a) is —NR^(5a)S(O)₂R^(5b), or —NR^(6a)R^(6b);

-   each R^(2b) is independently halo, alkyl, haloalkyl, —NO₂, or cyano;-   R³ is hydrogen, alkyl, or haloalkyl;-   R⁴ is hydrogen, alkyl, or haloalkyl;-   R^(5a) and R^(6a) are independently hydrogen or alkyl;-   R^(5b) and R^(6b) are independently alkyl; haloalkyl; cycloalkyl;    cycloalkylalkyl; heterocycloalkyl; or heterocycloalkylalkyl; and-   wherein each cycloalkyl, either alone or as part of another group,    is independently optionally substituted with one or two groups    independently selected from the group consisting of alkyl, halo, and    haloalkyl; or-   a pharmaceutically acceptable salt thereof.

In another aspect, provided is a compound of Formula (IV)

wherein R^(10a) is ethyl, n-propyl, isopropyl, —O—C₁₋₃ alkyl, —O—C₁₋₃alkoxy, pyrrolidine, or morpholine; R¹⁰ is H, halogen, —OH, —O—C₁₋₃alkyl, —O—C₁₋₃ alkoxy, —OC(O)R^(10d), or —NR^(10b)R^(10c); R^(10d) isC₁-C₃ alkyl or aryl; R^(10b) is H, C₁-C₃ alkyl, -alkyl-cyclopropane,cyclohexyl, benzyl, or —SO₂—R^(10e); R^(10c) is H, C₁-C₃ alkyl, or—SO₂—R¹⁰ e; and R^(10e) is alkyl or cycloalkyl.

In another aspect, provided herein are pharmaceutical compositions,single unit dosage forms, and kits suitable for use in treatingdisorders associated with abnormal activation of the SREBP pathway whichcomprise a therapeutically effective amount of a compound providedherein, e.g., of some or any of the embodiments, of Formula (I)-(Im),(100), (200), and (Ia-1)-(Im-1) and specific compounds 1-130, and apharmaceutically acceptable carrier thereof.

In another aspect, provided herein is a method of treating a condition,disease, or disorder associated with abnormal activation of the SREBPpathway comprising a) administering a therapeutically effective amountof a compound provided herein, e.g., of some or any of the embodiments,of Formula (I)-(Im), (100), (200), and (Ia-1)-(Im-1) and specificcompounds 1-130 or a pharmaceutically acceptable salt thereof or b)administering a therapeutically effective amount of a compositioncomprising a compound provided herein, e.g., of some or any of theembodiments, of Formula (I)-(Im), (100), (200), and (Ia-1)-(Im-1) andspecific compounds 1-130 or a pharmaceutically acceptable salt thereofand a pharmaceutically acceptable carrier thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A depicts results for several liver cell lines tested for growthinhibition by a test compound within the scope for Formula I.

FIG. 1B depicts results for several liver cell lines tested for growthinhibition by a test compound within the scope for Formula I.

FIG. 2A depicts results for a prostate cancer cell line tested forgrowth inhibition by a test compound within the scope for Formula I.

FIG. 2B depicts results for a prostate cancer cell line tested forgrowth inhibition by a test compound within the scope for Formula I.

FIG. 3A depicts results for leukemia cell lines tested for growthinhibition by a test compound within the scope for Formula I.

FIG. 3B depicts results for leukemia cell lines tested for growthinhibition by a test compound within the scope for Formula I.

FIG. 4A depicts results for body weight after ten weeks of treatmentwithin a test compound with the scope for Formula I.

FIG. 4B depicts results for lean content after ten weeks of treatmentwithin a test compound with the scope for Formula I.

FIG. 4C depicts results for fat content after ten weeks of treatmentwithin a test compound with the scope for Formula I.

FIG. 5 depicts results for glucose levels in blood of mice treated with0.25 and 2.5 mg/kg of a test compound within the scope for Formula I.

FIG. 6A depicts results for triglyceride levels in mice treated with atest compound within the scope for Formula I.

FIG. 6B depicts results for total cholesterol levels in mice treatedwith a test compound within the scope for Formula I.

FIG. 6C depicts results for HDL levels in mice treated with a testcompound within the scope for Formula I.

FIG. 6D depicts results for LDL levels in mice treated with a testcompound within the scope for Formula I.

FIG. 7A depicts results for levels of aspartate aminotransferase (AST)in serum of mice after nine weeks of treatment with a test compoundwithin the scope for Formula I.

FIG. 7B depicts results for levels of alanine aminotransferase (ALT) inserum of mice after nine weeks of treatment with a test compound withinthe scope for Formula I.

DESCRIPTION OF EXEMPLARY EMBODIMENTS Definitions

When referring to the compounds provided herein, the following termshave the following meanings unless indicated otherwise. Unless definedotherwise, all technical and scientific terms used herein have the samemeaning as is commonly understood by one of ordinary skill in the art.In the event that there is a plurality of definitions for a term herein,those in this section prevail unless stated otherwise. Unless specifiedotherwise, where a term is defined as being unsubstituted orsubstituted, the groups in the list of substituents are themselvesunsubstituted. For example, a substituted alkyl group can besubstituted, for example, with a cycloalkyl group, and the cycloalkylgroup is not further substituted unless specified otherwise.

“—O—C₁₋₃ Alkoxy” means an —OR group where R is C₁₋₃ alkyl substitutedwith C₁₋₃ alkoxy, as defined herein.

“Alkenyl” means a straight or branched hydrocarbon radical having from 2to 8 carbon atoms and at least one double bond, and in some embodiments,includes ethenyl, propenyl, 1-but-3-enyl, 1-pent-3-enyl, 1-hex-5-enyl,and the like. “Lower alkenyl” means an alkenyl group having one to sixcarbon atoms.

“Alkyl” means a linear or branched hydrocarbon group having one to eightcarbon atoms. “Lower alkyl” means an alkyl group having one to sixcarbon atoms. In some embodiments, lower alkyl includes methyl, ethyl,propyl, isopropyl, butyl, s-butyl, t-butyl, isobutyl, pentyl, hexyl, andthe like. A “Co” alkyl (as in “C₀-C₆-alkyl”) is a covalent bond. “C₆alkyl” refers to, for example, n-hexyl, iso-hexyl, and the like.

“Alkylamino” means a —NHR radical where R is alkyl as defined herein, oran N-oxide derivative thereof. In some embodiments, alkylamino includesmethylamino, ethylamino, n- or iso-propylamino, n-, iso-, ortert-butylamino, and methylamino-N-oxide, and the like.

“Amino” means a —NH₂.

“Aryl” means a monovalent six- to fourteen-membered, mono- orbi-carbocyclic ring, wherein the monocyclic ring is aromatic and atleast one of the rings in the bicyclic ring is aromatic. In someembodiments, aryl is phenyl, naphthyl, or indanyl, and the like.

“Cycloalkyl” means a monocyclic or polycyclic hydrocarbon radical havingthree to thirteen carbon atoms. The cycloalkyl can be saturated orpartially unsaturated, but cannot contain an aromatic ring. In someembodiments, cycloalkyl includes fused, bridged, and spiro ring systems.In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl,or cyclohexyl.

“Cycloalkylalkyl” means alkyl group substituted with one or twocycloalkyl group(s), as defined herein. In some embodiments,cycloalkylalkyl includes cyclopropylmethyl, 2-cyclobutyl-ethyl, and thelike.

“Dialkylamino” means a —NRR′ radical where R and R′ are independentlyalkyl as defined herein, and an N-oxide thereof. In some embodiments,dialkylamino includes dimethylamino, diethylamino, N,N-methylpropylaminoand N,N-methylethylamino, and the like.

“Haloalkyl” means an alkyl group, as defined herein, substituted withone or more halogens, for example, one, two, three, four, or five haloatoms. In some embodiments, haloalkyl includes 2,2-difluoroethyl,trifluoromethyl, 2-chloro-1-fluoroethyl, and the like.

“Heteroaryl” means a monocyclic, monovalent aromatic radical of 5 or 6ring atoms containing one or more heteroatoms, for example one, two, orthree ring heteroatoms, independently selected from oxygen, nitrogen,and sulfur and the remaining ring atoms being carbon. Unless statedotherwise, the point of attachment may be located on any atom of anyring of the heteroaryl group, valency rules permitting. In someembodiments, the term heteroaryl includes, but is not limited to,1,2,4-triazolyl, 1,3,5-triazolyl, pyridinyl, pyrrolyl, imidazolyl,thienyl, furanyl, tetrazoyl, pyrazolyl, pyrazinyl, pyrimidinyl,pyridazinyl, oxazolyl, isooxazolyl, oxadiazolyl, thiazolyl,isothiazolyl, thiadiazolyl, and an N-oxide thereof.

“Heterocycloalkyl” means a saturated or partially unsaturated (but notaromatic) monovalent monocyclic group of 3 to 9 ring atoms or asaturated or partially unsaturated (but not aromatic) monovalent fusedbicyclic group of 5 to 12 ring atoms in which one or more heteroatoms,for example one, two, three, or four ring heteroatoms, independentlyselected from —O—, —S(O)n- (n is 0, 1, or 2), —N═, —N(R^(y))— (whereR^(y) is hydrogen, alkyl, hydroxy, alkoxy, acyl, or alkylsulfonyl), theremaining ring atoms being carbon. One or two ring carbon atoms may bereplaced by a —C(O)—, —C(S)—, or —C(═NH)— group. Fused bicyclic radicalincludes bridged ring systems. Unless otherwise stated, the point ofattachment of the group may be located on any atom of any ring withinthe radical, valency rules permitting. In particular, when the point ofattachment is located on a nitrogen atom, R^(y) is absent. In someembodiments, the term heterocycloalkyl includes, but is not limited to,azetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, 2,5-dihydro-1H-pyrrolyl,piperidinyl, 4-piperidonyl, morpholinyl, piperazinyl, 2-oxopiperazinyl,tetrahydropyranyl, 2-oxopiperidinyl, thiomorpholinyl, thiamorpholinyl,perhydroazepinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,dihydropyridinyl, tetrahydropyridinyl, oxazolinyl, oxazolidinyl,isoxazolidinyl, thiazolinyl, thiazolidinyl, quinuclidinyl,isothiazolidinyl, octahydroindolyl, octahydroisoindolyl,decahydroisoquinolyl, tetrahydrofuryl, and tetrahydropyranyl, and anN-oxide thereof. In some embodiments, the heterocycloalkyl issubstituted on the nitrogen with R^(y) where R^(y) is alkyl.

“Heterocycloalkylalkyl” means an alkyl group, as defined herein,substituted with one or two heterocycloalkyl group(s), as definedherein.

“Patient” or “subject” includes humans and other animals, particularlymammals, and other organisms. Thus the methods are applicable to bothhuman therapy and veterinary applications. In some embodiments thepatient is a mammal, and in other embodiments the patient is human.

A “pharmaceutically acceptable salt” of a compound means a salt that ispharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. It is understood thatthe pharmaceutically acceptable salts are non-toxic. Additionalinformation on suitable pharmaceutically acceptable salts can be foundin Remington's Pharmaceutical Sciences, 17^(th) ed., Mack PublishingCompany, Easton, Pa., 1985, which is incorporated herein by reference,or S. M. Berge et al., “Pharmaceutical Salts,” J. Pharm. Sci. 1977; 66,1-19 which is also incorporated herein by reference. It is alsounderstood that the compound can have one or more pharmaceuticallyacceptable salts associated with it.

Examples of pharmaceutically acceptable acid addition salts includethose formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, and the like; as wellas organic acids such as acetic acid, trifluoroacetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvicacid, lactic acid, oxalic acid, maleic acid, malonic acid, succinicacid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamicacid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonicacid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, p-toluenesulfonic acid, salicylicacid, and the like.

Examples of a pharmaceutically acceptable base addition salts includethose formed when an acidic proton present in the parent compound isreplaced by a metal ion, such as sodium, potassium, lithium, ammonium,calcium, magnesium, iron, zinc, copper, manganese, and aluminum, assalts, and the like. Preferable salts are the ammonium, potassium,sodium, calcium, and magnesium salts. Salts derived frompharmaceutically acceptable organic non-toxic bases include, but are notlimited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins. Examples of organic basesinclude isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine,glucosamine, methylglucamine, theobromine, purines, piperazine,piperidine, N-ethylpiperidine, tromethamine, N-methylglucamine,polyamine resins, and the like. Exemplary organic bases areisopropylamine, diethylamine, ethanolamine, trimethylamine,dicyclohexylamine, choline, and caffeine.

The term “substantially free of” or “substantially in the absence of”stereoisomers with respect to a composition refers to a composition thatincludes at least 85 or 90% by weight, in certain embodiments 95%, 98%,99% or 100% by weight, of a designated stereoisomer of a compound in thecomposition. In certain embodiments, in the methods and compoundsprovided herein, the compounds are substantially free of stereoisomers.

Similarly, the term “isolated” with respect to a composition refers to acomposition that includes at least 85, 90%, 95%, 98%, 99% to 100% byweight, of a specified compound, the remainder comprising other chemicalspecies or stereoisomers.

The term “solvate,” as used herein, and unless otherwise specified,refers to a compound provided herein, or a salt thereof, that furtherincludes a stoichiometric or non-stoichiometric amount of solvent boundby non-covalent intermolecular forces. In one embodiment, where thesolvent is water, the solvate is a hydrate.

The term “isotopic composition,” as used herein, and unless otherwisespecified, refers to the amount of each isotope present for a givenatom, and “natural isotopic composition” refers to the naturallyoccurring isotopic composition or abundance for a given atom. Atomscontaining their natural isotopic composition may also be referred toherein as “non-enriched” atoms. Unless otherwise designated, the atomsof the compounds recited herein are meant to represent any stableisotope of that atom. For example, unless otherwise stated, when aposition is designated specifically as “H” or “hydrogen,” the positionis understood to have hydrogen at its natural isotopic composition.

The term “isotopic enrichment,” as used herein, and unless otherwisespecified, refers to the percentage of incorporation of an amount of aspecific isotope at a given atom in a molecule in the place of thatatom's natural isotopic abundance. In certain embodiments, deuteriumenrichment of 1% at a given position means that 1% of the molecules in agiven sample contain deuterium at the specified position. Because thenaturally occurring distribution of deuterium is about 0.0156%,deuterium enrichment at any position in a compound synthesized usingnon-enriched starting materials is about 0.0156%. The isotopicenrichment of the compounds provided herein can be determined usingconventional analytical methods known to one of ordinary skill in theart, including mass spectrometry and nuclear magnetic resonancespectroscopy.

The term “isotopically enriched,” as used herein, and unless otherwisespecified, refers to an atom having an isotopic composition other thanthe natural isotopic composition of that atom. “Isotopically enriched”may also refer to a compound containing at least one atom having anisotopic composition other than the natural isotopic composition of thatatom.

As used herein, “alkyl,” “cycloalkyl,” “aryl,” “alkoxy,”“heterocycloalkyl,” “heterocyclic,” and “heteroaryl,” groups optionallycomprise deuterium at one or more positions where hydrogen atoms arepresent, and wherein the deuterium composition of the atom or atoms isother than the natural isotopic composition.

Also as used herein, “alkyl,” “cycloalkyl,” “aryl,” “alkoxy,”“heterocycloalkyl,” “heterocyclic,” and “heteroaryl,” groups optionallycomprise carbon-13 at an amount other than the natural isotopiccomposition.

As used herein, the terms “subject” and “patient” are usedinterchangeably. The terms “subject” and “subjects” refer to an animal,such as a mammal including a non-primate (e.g., a cow, pig, horse, cat,dog, rat, and mouse) and a primate (e.g., a monkey such as a cynomolgousmonkey, a chimpanzee, and a human), and in certain embodiments, a human.In certain embodiments, the subject is a farm animal (e.g., a horse, acow, a pig, etc.) or a pet (e.g., a dog or a cat). In certainembodiments, the subject is a human.

“Administration” and variants thereof (e.g., in some embodiments,“administering” a compound) in reference to a compound of the inventionmeans introducing the compound or a prodrug thereof into the system ofthe animal in need of treatment. When a compound of the invention orprodrug thereof is provided in combination with one or more other activeagents (e.g., in some embodiments, surgery, radiation, and chemotherapy,etc.), “administration” and its variants are each understood to includeconcurrent and sequential introduction of the compound or prodrugthereof and other agents.

“Therapeutically effective amount” is an amount of a compound orcomposition, that when administered to a patient, is sufficient toeffect such treatment for the condition, disease, or disorder, e.g., toameliorate a symptom of the disease. The amount of a compound of theinvention which constitutes a “therapeutically effective amount” willvary depending on the compound, the disease state and its severity, theage of the patient to be treated, and the like. The therapeuticallyeffective amount can be determined routinely by one of ordinary skill inthe art having regard to their knowledge and to this disclosure.

As used herein, the terms “therapeutic agent” and “therapeutic agents”refer to any agent(s) which can be used in the treatment or preventionof a disorder or one or more symptoms thereof. In certain embodiments,the term “therapeutic agent” includes a compound provided herein. Incertain embodiments, a therapeutic agent is an agent that is known to beuseful for, or has been or is currently being used for the treatment orprevention of a disorder or one or more symptoms thereof.

“Treating” or “treatment” of a disease, disorder, or syndrome, as usedherein, includes (i) preventing the disease, disorder, or syndrome fromoccurring in a human, i.e., causing the clinical symptoms of thedisease, disorder, or syndrome not to develop in an animal that may beexposed to or predisposed to the disease, disorder, or syndrome, butdoes not yet experience or display symptoms of the disease, disorder, orsyndrome; (ii) inhibiting the disease, disorder, or syndrome, i.e.,arresting its development; and (iii) relieving the disease, disorder, orsyndrome, e.g., relieving or reducing a symptom thereof, and/or causingregression of the disease, disorder, or syndrome. As is known in theart, adjustments for systemic versus localized delivery, age, bodyweight, general health, sex, diet, time of administration, druginteraction and the severity of the condition, disease, or disorder maybe necessary, and will be ascertainable with routine experimentation byone of ordinary skill in the art. “Treating” or “treatment” of anycondition, disease, or disorder refers, in certain embodiments, toameliorating a condition, disease, or disorder that exists in a subject.In another embodiment, “treating” or “treatment” includes amelioratingat least one physical parameter, which may be indiscernible by thesubject. In yet another embodiment, “treating” or “treatment” includesmodulating the condition, disease, or disorder, either physically (e.g.,stabilization of a discernible symptom) or physiologically (e.g.,stabilization of a physical parameter) or both. In yet anotherembodiment, “treating” or “treatment” includes delaying the onset of thecondition, disease, or disorder.

As used herein, the terms “prophylactic agent” and “prophylactic agents”refer to any agent(s) which can be used in the prevention of acondition, disease, or disorder, or one or more symptoms thereof. Incertain embodiments, the term “prophylactic agent” includes a compoundprovided herein. In certain other embodiments, the term “prophylacticagent” does not refer a compound provided herein. In certainembodiments, a prophylactic agent can be an agent that is known to beuseful for, or has been or is currently being used to prevent or impedethe onset, development, progression, and/or severity of a condition,disease, or disorder.

As used herein, the phrase “prophylactically effective amount” refers tothe amount of a therapy (e.g., prophylactic agent) which is sufficientto result in the prevention or reduction of the development, recurrenceor onset of one or more symptoms associated with a condition, disease,or disorder, or to enhance or improve the prophylactic effect(s) ofanother therapy (e.g., another prophylactic agent).

Compounds

The embodiments described herein include the recited compounds as wellas a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer,tautomer, or mixture thereof.

In some or any embodiments, the Compound (e.g., of Formula (I), (100),(Ia), (Ib), and (Ih), and any embodiments thereof) is notN-methyl-6-(1-phenyl-1H-pyrazol-4-yl)pyridazin-3-amine;N-ethyl-6-(1-phenyl-1H-pyrazol-4-yl)pyridazin-3-amine; orN-propyl-6-(1-phenyl-1H-pyrazol-4-yl)pyridazin-3-amine.

In one aspect, provided is a Compound of Formula (100):

where

-   R¹ is phenyl, pyridinonyl, pyridinyl, pyrimidinyl, pyridazinyl, or    pyrazinyl; where the phenyl, the pyridinyl, pyrimidinyl,    pyridazinyl, and pyrazinyl rings are optionally substituted with 1    or 2 R^(1a) and where the pyridinonyl is substituted on the nitrogen    with R^(1b) and is additionally optionally substituted with 1    R^(1a);-   each R^(1a) is independently halo, alkyl, alkenyl, haloalkyl,    cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or    heterocycloalkylalkyl;-   R^(1b) is hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl,    cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl;-   R² is

where 0, 1, or 2 of X¹-X⁴ are nitrogen and the remaining are carbon;

-   R^(2a) is —NR^(5a)S(O)₂R^(5b) or —NR^(6a)R^(6b);-   each R^(2b) is independently halo, alkyl, haloalkyl, —NO₂, or cyano;-   R³ is hydrogen, halo, alkyl, or haloalkyl;-   R⁴ is hydrogen, halo, alkyl, or haloalkyl;-   R^(5a) and R^(6a) are independently hydrogen or alkyl; and-   R^(5b) and R^(6b) are independently alkyl; haloalkyl; cycloalkyl    where the cycloalkyl is optional substituted with 1 or 2 alkyl    groups; cycloalkylalkyl; heterocycloalkyl; heterocycloalkylalkyl; or-   a pharmaceutically acceptable salt thereof,-   provided that the compound is not    N-methyl-6-(1-phenyl-1H-pyrazol-4-yl)pyridazin-3-amine;    N-ethyl-6-(1-phenyl-1H-pyrazol-4-yl)pyridazin-3-amine; or    N-propyl-6-(1-phenyl-1H-pyrazol-4-yl)pyridazin-3-amine.

In another aspect, provided is a Compound according to Formula (200)

where

-   R¹ is phenyl, pyridinonyl, pyridinyl, pyrimidinyl, pyridazinyl, or    pyrazinyl; where the R¹ phenyl, pyridinyl, pyrimidinyl, pyridazinyl,    and pyrazinyl rings are substituted with one R^(1a) and additionally    optionally substituted with a second R^(1a), and where the    pyridinonyl is substituted on the nitrogen with R^(1b) and is    additionally optionally substituted with 1 R^(1a);-   each R^(1a) is independently halo, alkyl, haloalkyl, or    heterocycloalkyl;-   R^(1b) is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl,    or heterocycloalkyl;-   R²⁰ is

where 0, 1, or 2 of X¹-X⁴ are nitrogen and the remaining are carbon;each R^(2b) is independently halo, alkyl, haloalkyl, —NO₂, or cyano;

-   R^(2c) is —NO₂ or NH₂;-   R³ is hydrogen or alkyl;-   R⁴ is hydrogen or alkyl;-   R^(5a) and R^(6a) are independently hydrogen or alkyl; and-   R^(5b) and R^(6b) are independently alkyl, haloalkyl, cycloalkyl,    cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl; or-   a pharmaceutically acceptable salt thereof,-   provided that the compound is not    4-(1-(3-methylpyridin-4-yl)-1H-pyrazol-4-yl)aniline;    4-(1-(2-methylpyridin-4-yl)-1H-pyrazol-4-yl)aniline; or    4-(1-(3-chloropyridin-4-yl)-1H-pyrazol-4-yl)aniline.

In another aspect, provided is a Compound according to Formula (300)

where

-   PG¹ is a nitrogen protecting group;-   R² is

where 0, 1, or 2 of X¹-X⁴ are nitrogen and the remaining are carbon;

-   R^(2a) is —NR^(5a)S(O)₂R^(5b), or —NR^(6a)R^(6b);-   each R^(2b) is independently halo, alkyl, haloalkyl, —NO₂, or cyano;-   R³ is hydrogen or alkyl;-   R⁴ is hydrogen or alkyl;-   R^(5a) and R^(6a) are independently hydrogen or alkyl;-   R^(5b) and R^(6b) are independently alkyl; haloalkyl; cycloalkyl;    cycloalkylalkyl where the cycloalkyl is optionally substituted with    1 or 2 alkyl groups; heterocycloalkyl; or heterocycloalkylalkyl; or-   a pharmaceutically acceptable salt thereof.

In one embodiment, provided is a Compound of Formula (I):

where

-   R¹ is phenyl, pyridinonyl, or pyridinyl; where the phenyl,    pyridinonyl, and pyridinyl rings are optionally substituted with 1    R^(1a) and where the pyridinonyl is substituted on the nitrogen with    R^(1b);-   R^(1a) is alkyl, haloalkyl, or heterocycloalkyl;-   R^(1b) is alkyl, haloalkyl, or cycloalkylalkyl;-   R² is

-   R^(2a) is —NR^(5a)S(O)₂R^(5b), or —NR^(6a)R^(6b);-   R^(2b) is halo, alkyl, haloalkyl, or cyano;-   R³ is hydrogen or alkyl;-   R⁴ is hydrogen or alkyl;-   R^(5a) and R^(6a) are hydrogen; and-   R^(5b) and R^(6b) are independently alkyl; haloalkyl; cycloalkyl    where the cycloalkyl is optionally substituted with 1 or 2 alkyl    groups; cycloalkylalkyl; or heterocycloalkyl; or-   a pharmaceutically acceptable salt thereof.

In one embodiment, provided is a Compound of Formula (I):

where

-   R¹ is phenyl, pyridinonyl, or pyridinyl; where the phenyl,    pyridinonyl, and pyridinyl rings are optionally substituted with 1    R^(1a) and where the pyridinonyl is substituted on the nitrogen with    R^(1b);-   R^(1a) is alkyl, haloalkyl, or heterocycloalkyl;-   R^(1b) is alkyl;-   R² is

-   R^(2a) is —NR^(5a)S(O)₂R^(5b) or —NR^(6a)R^(6b);-   R^(2b) is halo, alkyl, haloalkyl, or cyano;-   R³ is hydrogen or alkyl;-   R⁴ is hydrogen or alkyl;-   R^(5a) and R^(6a) are hydrogen; and-   R^(5b) and R^(6b) are independently alkyl; haloalkyl; cycloalkyl;    cycloalkylalkyl; or heterocycloalkyl; or    a pharmaceutically acceptable salt thereof.

In some or any embodiments, the Compound (e.g., of Formula (I), (100),(Ia), (Ic), (Ie), (If), (Ia-1), (Ic-1), and (Ie-1), and any embodimentsthereof) is not

In some or any embodiments, the Compound (e.g., of Formula (I), (100),(Ia), (Ic), (Ie), (If), (Ia-1), (Ic-1), and (Ie-1), and any embodimentsthereof) is not a pharmaceutically acceptable salt of one of thespecific compounds in this paragraph.

In some or any embodiments, the Compound (e.g., of Formula (I), (100),(Ia), (Ib), (Ic), (Ie), (If), (Ih), (Ia-1), (Ic-1), and (Ie-1), and anyembodiments thereof) is notN-methyl-6-(1-phenyl-1H-pyrazol-4-yl)pyridazin-3-amine;N-ethyl-6-(1-phenyl-1H-pyrazol-4-yl)pyridazin-3-amine; orN-propyl-6-(1-phenyl-1H-pyrazol-4-yl)pyridazin-3-amine; and not

In some embodiments, the Compound (e.g., of Formula (I), (100), (Ia),(Ib), (Ic), (Ie), (If), (Ih), (Ia-1), (Ic-1), and (Ie-1), and anyembodiments thereof) is not a pharmaceutically acceptable salt of one ofthe specific compounds in this paragraph.

A Compound according to Formula (Ia):

where R¹, R², R³, R⁴, and all other groups are as defined in the Summaryof the Invention for a Compound of Formula (I) or in any embodimentsdescribed herein; or a pharmaceutically acceptable salt thereof. In someor any embodiments, the Compound of Formula (Ia) is that where R² is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (Ia) is that where R³and R⁴ are hydrogen.

In some or any embodiments, the Compound is according to Formula (Ib):

where R^(1a), R², R³, R⁴, and all other groups are as defined in theSummary of the Invention for a Compound of Formula (I) or in anyembodiments described herein; or a pharmaceutically acceptable saltthereof. In some or any embodiments, the Compound of Formula (Ib) isthat where R² is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (Ib) is that where R³and R⁴ are hydrogen.

In some or any embodiments, the Compound is according to Formula (Ic):

where R^(1a), R², R³, R⁴, and all other groups are as defined in theSummary of the Invention for a Compound of Formula (I) or in anyembodiments described herein; or a pharmaceutically acceptable saltthereof. In some or any embodiments, the Compound of Formula (Ic) isthat where R² is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (Ic) is that where R³and R⁴ are hydrogen.

In some or any embodiments, the Compound is according to Formula (Id):

where R^(1a), R^(1b), R², R³, R⁴, and all other groups are as defined inthe Summary of the Invention for a Compound of Formula (I) or in anyembodiments described herein; or a pharmaceutically acceptable saltthereof. In some or any embodiments, the Compound of Formula (Id) isthat where R² is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (Id) is that where R²is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (Id) is that where R²is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (Id) is that where R²is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (Id) is that where R²is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (Id) is that where R³and R⁴ are hydrogen.

In some or any embodiments, the Compound is according to Formula (Ie):

where R¹, R^(2a), R^(2b), R³, R⁴, and all other groups are as defined inthe Summary of the Invention for a Compound of Formula (I) or in anyembodiments described herein; or a pharmaceutically acceptable saltthereof. In some or any embodiments, the Compound of Formula (Ie) isthat wherein R¹ is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (Ie) is that wherein R¹is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (Ie) is that where R³and R⁴ are hydrogen. In some or any embodiments, the Compound of Formula(Ie) is that where one R^(2b) is present.

In some or any embodiments, the Compound is according to Formula (If):

where R¹, R^(2a), R^(2b), R³, R⁴, and all other groups are as defined inthe Summary of the Invention for a Compound of Formula (I) or in anyembodiments described herein; or a pharmaceutically acceptable saltthereof. In some or any embodiments, the Compound of Formula (If) isthat wherein R¹ is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (If) is that wherein R¹is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (If) is that where R³and R⁴ are hydrogen. In some or any embodiments, the Compound of Formula(If) is that where one R^(2b) is present.

In some or any embodiments, the Compound is according to Formula (Ig):

where R¹, R^(2a), R^(2b), R³, R⁴, and all other groups are as defined inthe Summary of the Invention for a Compound of Formula (I) or in anyembodiments described herein; or a pharmaceutically acceptable saltthereof. In some or any embodiments, the Compound of Formula (Ig) isthat wherein R¹ is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (Ig) is that where R³and R⁴ are hydrogen. In some or any embodiments, the Compound of Formula(Ig) is that where one R^(2b) is present.

In some or any embodiments, the Compound is according to Formula (Ih):

where R¹, R^(2a), R^(2b), R³, R⁴, and all other groups are as defined inthe Summary of the Invention for a Compound of Formula (I) or in anyembodiments described herein; or a pharmaceutically acceptable saltthereof. In some or any embodiments, the Compound of Formula (Ih) isthat wherein R¹ is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (Ih) is that where R³and R⁴ are hydrogen. In some or any embodiments, the Compound of Formula(Ih) is that where one R^(2b) is present.

In some or any embodiments, the Compound is according to Formula (Ij):

where R¹, R^(2a), R^(2b), R³, R⁴, and all other groups are as defined inthe Summary of the Invention for a Compound of Formula (I) or in anyembodiments described herein; or a pharmaceutically acceptable saltthereof. In some or any embodiments, the Compound of Formula (Ij) isthat wherein R¹ is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (Ij) is that where R³and R⁴ are hydrogen. In some or any embodiments, the Compound of Formula(Ij) is that where one R^(2b) is present.

In some or any embodiments, the Compound is according to Formula (Ik):

where R¹, R^(2a), R^(2b), R³, R⁴, and all other groups are as defined inthe Summary of the Invention for a Compound of Formula (I) or in anyembodiments described herein; or a pharmaceutically acceptable saltthereof. In some or any embodiments, the Compound of Formula (Ik) isthat wherein R¹ is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (Ik) is that where R³and R⁴ are hydrogen. In some or any embodiments, the Compound of Formula(Ik) is that where one R^(2b) is present.

In some or any embodiments, the Compound is according to Formula (Im):

where R¹, R^(2a), R^(2b), R³, R⁴, and all other groups are as defined inthe Summary of the Invention for a Compound of Formula (I) or in anyembodiments described herein; or a pharmaceutically acceptable saltthereof. In some or any embodiments, the Compound of Formula (Im) isthat wherein R¹ is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (Im) is that where R³and R⁴ are hydrogen. In some or any embodiments, the Compound of Formula(Im) is that where one R^(2b) is present. In some or any embodiments,the Compound of Formula (Im) is that where no R^(2b) is present.

In some or any embodiments, the Compound of Formula (I), (100), (Ia),(Ib), or (Ih) is notN-methyl-6-(1-phenyl-1H-pyrazol-4-yl)pyridazin-3-amine;N-ethyl-6-(1-phenyl-1H-pyrazol-4-yl)pyridazin-3-amine; orN-propyl-6-(1-phenyl-1H-pyrazol-4-yl)pyridazin-3-amine.

In some or any embodiments, the Compound of Formula (I), (100), (Ia),(Ib), (Ic), (Ie), (If), or (Ih) is notN-methyl-6-(1-phenyl-1H-pyrazol-4-yl)pyridazin-3-amine;N-ethyl-6-(1-phenyl-1H-pyrazol-4-yl)pyridazin-3-amine; orN-propyl-6-(1-phenyl-1H-pyrazol-4-yl)pyridazin-3-amine; and not

In some or any embodiments, the Compound (e.g., of Formula (I), (100),(Ia), (Ib), (Ic), (Ie), (If), or (Ih), and any embodiments thereof) isnot a pharmaceutically acceptable salt of one of the specific compoundsin this paragraph.

In some or any embodiments, the Compound of Formula (I)-(Im), (100), or(Ia-1)-(Im-1) is that where R³ and R⁴ are hydrogen; R³ and R⁴ are alkyl;or one of R³ and R⁴ is hydrogen and the other is alkyl; and all othergroups are as defined in the Summary of the Invention for a Compound ofFormula (I) or in any embodiments described herein. In some or anyembodiments, the Compound of Formula (I)-(Im), (100), or (Ia-1)-(Im-1)is that where R³ and R⁴ are hydrogen; R³ and R⁴ are methyl; R³ ishydrogen and R⁴ is methyl; or R³ is methyl and R⁴ is hydrogen; and allother groups are as defined in the Summary of the Invention for aCompound of Formula (I) or in any embodiments described herein. In someor any embodiments, the Compound of Formula (I)-(Im), (100), or(Ia-1)-(Im-1) is that where R³ and R⁴ are hydrogen; and all other groupsare as defined in the Summary of the Invention for a Compound of Formula(I) or in any embodiments described herein.

In some or any embodiments, the Compound of Formula (I), (Ia), (Ie),(If), (Ig), (Ih), (Ij), (Ik), (Im), (100), (Ia-1), (Ie-1), (If-1),(Ig-1), (Ih-1), (Ij-1), (Ik-1), or (Im-1) is that where R¹ is phenyl,pyridinonyl, or pyridinyl; where the phenyl and pyridinyl rings areoptionally substituted with 1 or 2 R^(1a) and where the pyridinonyl issubstituted on the nitrogen with R^(1b) and is additionally optionallysubstituted with 1 R^(1a); and all other groups are as defined in theSummary of the Invention for a Compound of Formula (I) or in anyembodiments described herein.

In some or any embodiments, the Compound of Formula (I), (Ia), (Ie),(If), (Ig), (Ih), (Ij), (Ik), (Im), (100), (Ia-1), (Ie-1), (If-1),(Ig-1), (Ih-1), (Ij-1), (Ik-1), or (Im-1) is that where R¹ ispyridinonyl substituted on the nitrogen with R^(1b) and additionallyoptionally substituted with 1 R^(1a); and all other groups are asdefined in the Summary of the Invention for a Compound of Formula (I) orin any embodiments described herein.

In some or any embodiments, the Compound of Formula (I), (Ia), (Ie),(If), (Ig), (Ih), (Ij), (Ik), (Im), (100), (Ia-1), (Ie-1), (If-1),(Ig-1), (Ih-1), (Ij-1), (Ik-1), or (Im-1) is that where R¹ is phenyloptionally substituted with 1 or 2 R^(1a); and all other groups are asdefined in the Summary of the Invention for a Compound of Formula (I) orin any embodiments described herein.

In some or any embodiments, the Compound of Formula (I), (Ia), (Ie),(If), (Ig), (Ih), (Ij), (Ik), (Im), (100), (Ia-1), (Ie-1), (If-1),(Ig-1), (Ih-1), (Ij-1), (Ik-1), or (Im-1) is that where R¹ is pyridinyloptionally substituted with 1 or 2 R^(1a); and all other groups are asdefined in the Summary of the Invention for a Compound of Formula (I) orin any embodiments described herein.

In some or any embodiments, the Compound of Formula (I), (Ia), (Ie),(If), (Ig), (Ih), (Ij), (Ik), (Im), (100), (Ia-1), (Ie-1), (If-1),(Ig-1), (Ih-1), (Ij-1), (Ik-1), or (Im-1) is that where R¹ ispyrimidinyl optionally substituted with 1 or 2 R^(1a); and all othergroups are as defined in the Summary of the Invention for a Compound ofFormula (I) or in any embodiments described herein.

In some or any embodiments, the Compound of Formula (I), (Ia), (Ie),(If), (Ig), (Ih), (Ij), (Ik), (Im), (100), (Ia-1), (Ie-1), (If-1),(Ig-1), (Ih-1), (Ij-1), (Ik-1), or (Im-1) is that where R¹ ispyridazinyl optionally substituted with 1 or 2 R^(1a); and all othergroups are as defined in the Summary of the Invention for a Compound ofFormula (I) or in any embodiments described herein.

In some or any embodiments, the Compound of Formula (I), (Ia), (Ie),(If), (Ig), (Ih), (Ij), (Ik), (Im), (100), (Ia-1), (Ie-1), (If-1),(Ig-1), (Ih-1), (Ij-1), (Ik-1), or (Im-1) is that where R¹ is pyrazinyloptionally substituted with 1 or 2 R^(1a); and all other groups are asdefined in the Summary of the Invention for a Compound of Formula (I) orin any embodiments described herein.

In some or any embodiments, the Compound of Formula (I), (Ia), (Ib),(Ic), (Id), (100), (Ia-1), (Ib-1), (Ic-1), or (Id-1) is that where R² is

where 0, 1, or 2 of X¹-X⁴ are nitrogen and the remaining are carbon; andall other groups are as defined in the Summary of the Invention for aCompound of Formula (I) or in any embodiments described herein. In someof any embodiment, the Compound of Formula (I), (Ia), (Ib), (Ic), (Id),(100), (Ia-1), (Ib-1), (Ic-1), or (Id-1) is that where R² is

where 0, 1, or 2 of X¹, X³, and X⁴ are nitrogen and the remaining arecarbon; and all other groups are as defined in the Summary of theInvention for a Compound of Formula (I) or in any embodiments describedherein. In some of any embodiment, the Compound of Formula (I), (Ia),(Ib), (Ic), (Id), (100), (Ia-1), (Ib-1), (Ic-1), or (Id-1) is that whereR² is

where 0, 1, or 2 of X², X³, and X⁴ are nitrogen and the remaining arecarbon; and all other groups are as defined in the Summary of theInvention for a Compound of Formula (I) or in any embodiments describedherein.

In some or any embodiments, the Compound of Formula (I), (Ia), (Ib),(Ic), (Id), (100), (Ia-1), (Ib-1), (Ic-1), or (Id-1) is that where R² is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (I), (Ia), (Ib), (Ic),(Id), (100), (Ia-1), (Ib-1), (Ic-1), or (Id-1) is that where R² is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (I), (Ia), (Ib), (Ic),(Id), (100), (Ia-1), (Ib-1), (Ic-1), or (Id-1) is that where R² is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (I), (Ia), (Ib), (Ic),(Id), (100), (Ia-1), (Ib-1), (Ic-1), or (Id-1) is that where R² is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein.

In some or any embodiments, the Compound of Formula (I), (Ia), (Ib),(Ic), (Id), (100), (Ia-i), (Ib-1), (Ic-1), or (Id-1) is that where R² is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (I), (Ia), (Ib), (Ic),(Id), (100), (Ia-1), (Ib-1), (Ic-1), or (Id-1) is that where R² is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (I), (Ia), (Ib), (Ic),(Id), (100), (Ia-1), (Ib-1), (Ic-1), or (Id-1) is that where R² is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (I), (Ia), (Ib), (Ic),(Id), (100), (Ia-1), (Ib-1), (Ic-1), or (Id-1) is that where R² is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (I), (Ia), (Ib), (Ic),(Id), (100), (Ia-1), (Ib-1), (Ic-1), or (Id-1) is that where R² is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein.

In some or any embodiments, the Compound of Formula (I), (Ia), (Ib),(Ic), (Id), (100), (Ia-1), (Ib-1), (Ic-1), or (Id-1) is that where R² is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (I), (Ia), (Ib), (Ic),(Id), (100), (Ia-1), (Ib-1), (Ic-1), or (Id-1) is that where R² is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (I), (Ia), (Ib), (Ic),(Id), (100), (Ia-1), (Ib-1), (Ic-1), or (Id-1) is that where R² is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein.

In some or any embodiments, the Compound of Formula (I), (Ia), (Ib),(Ic), (Id), (100), (Ia-1), (Ib-1), (Ic-1), or (Id-1) is that where R² is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (I), (Ia), (Ib), (Ic),(Id), (100), (Ia-1), (Ib-1), (Ic-1), or (Id-1) is that where R² is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (I), (Ia), (Ib), (Ic),(Id), (100), (Ia-1), (Ib-1), (Ic-1), or (Id-1) is that where R² is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (I), (Ia), (Ib), (Ic),(Id), (100), (Ia-1), (Ib-1), (Ic-1), or (Id-1) is that where R² is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein.

In some or any embodiments, the Compound of Formula (I), (Ia), (Ib),(Ic), (Id), (100), (Ia-1), (Ib-1), (Ic-1), or (Id-1) is that where R² is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (I), (Ia), (Ib), (Ic),(Id), (100), (Ia-1), (Ib-1), (Ic-1), or (Id-1) is that where R² is

and and all other groups are as defined in the Summary of the Inventionfor a Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (I), (Ia), (Ib), (Ic),(Id), (100), (Ia-1), (Ib-1), (Ic-1), or (Id-1) is that where R² is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (I), (Ia), (Ib), (Ic),(Id), (100), (Ia-1), (Ib-1), (Ic-1), or (Id-1) is that where R² is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein.

In some or any embodiments, the Compound of Formula (I), (Ia), (Ib),(Ic), (Id), (100), (Ia-1), (Ib-1), (Ic-1), or (Id-1) is that where R² is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (I), (Ia), (Ib), (Ic),(Id), (100), (Ia-1), (Ib-1), (Ic-1), or (Id-1) is that where R² is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (I), (Ia), (Ib), (Ic),(Id), (100), (Ia-1), (Ib-1), (Ic-1), or (Id-1) is that where R² is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (I), (Ia), (Ib), (Ic),(Id), (100), (Ia-1), (Ib-1), (Ic-1), or (Id-1) is that where R² is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein.

In some or any embodiments, the Compound of Formula (I)-(Im), (100), or(Ia-1)-(Im-1) is that where R^(2a) is —NR^(5a)S(O)₂R^(5b); and all othergroups are as defined in the Summary of the Invention for a Compound ofFormula (I) or in any embodiments described herein. In some or anyembodiments, the Compound of Formula (I)-(Im), (100), or (Ia-1)-(Im-1)is that where R^(2a) is —NHS(O)₂R^(5b); and all other groups are asdefined in the Summary of the Invention for a Compound of Formula (I) orin any embodiments described herein.

In some or any embodiments, the Compound of Formula (I)-(Im), (100), or(Ia-1)-(Im-1) is that where R^(2a) is —NR^(6a)R^(6b); and all othergroups are as defined in the Summary of the Invention for a Compound ofFormula (I) or in any embodiments described herein. In some or anyembodiments, the Compound of Formula (I)-(Im), (100), or (Ia-1)-(Im-1)is that where R² is —NHR^(6b); and all other groups are as defined inthe Summary of the Invention for a Compound of Formula (I) or in anyembodiments described herein.

In some or any embodiments, the Compound of Formula (I), (Ia), (Ie),(If), (Ig), (Ih), (Ij), (Ik), (Im), (100), (Ia-1), (Ie-1), (If-1),(Ig-1), (Ih-1), (Ij-1), (Ik-1), or (Im-1) is that where R¹ is phenyl,pyridinonyl, or pyridinyl; where the phenyl and pyridinyl rings areoptionally substituted with 1 or 2 R^(1a) and where the pyridinonyl issubstituted on the nitrogen with R^(1b) and is additionally optionallysubstituted with 1 R^(1a); R³ and R⁴ are hydrogen; and all other groupsare as defined in the Summary of the Invention for a Compound of Formula(I) or in any embodiments described herein.

In some or any embodiments, the Compound of Formula (I), (Ia), (Ie),(If), (Ig), (Ih), (Ij), (Ik), (Im), (100), (Ia-1), (Ie-1), (If-1),(Ig-1), (Ih-1), (Ij-1), (Ik-1), or (Im-1) is that where R¹ is phenyl,pyridinonyl, or pyridinyl; where the phenyl and pyridinyl rings aresubstituted with 1 or 2 R^(1a) and where the pyridinonyl is substitutedon the nitrogen with R^(1b) and is additionally optionally substitutedwith 1 R^(1a); R³ and R⁴ are hydrogen; and all other groups are asdefined in the Summary of the Invention for a Compound of Formula (I) orin any embodiments described herein.

In some or any embodiments, the Compound of Formula (I), (Ia), (Id),(Ie), (If), (Ig), (Ih), (Ij), (Ik), (Im), (100), (Ia-1), (Id-1), (Ie-1),(If-1), (Ig-1), (Ih-1), (Ij-1), (Ik-1), or (Im-1) is that where R¹ ispyridinonyl substituted on the nitrogen with Rib and additionallyoptionally substituted with 1 R^(1a); and R^(1b) is alkyl, haloalkyl,cycloalkylalkyl, or heterocycloalkylalkyl where the heterocycloalkyl issubstituted with R^(y) where R^(y) is hydrogen, alkyl, hydroxy, alkoxy,acyl, or alkylsulfonyl; and all other groups are as defined in theSummary of the Invention for a Compound of Formula (I) or in anyembodiments described herein.

In some or any embodiments, provided is a Compound of Formula (I), (Ia),(Id), (Ie), (If), (Ig), (Ih), (Ij), (Ik), (Im), (100), (Ia-1), (Id-1),(Ie-1), (If-1), (Ig-1), (Ih-1), (Ij-1), (Ik-1), or (Im-1) where R^(1b)and additionally optionally substituted with 1 R^(1a); and R^(1b) isalkyl, haloalkyl, cycloalkylalkyl, or heterocycloalkylalkyl where theheterocycloalkyl is substituted with R^(y) where R^(y) is hydrogen,alkyl, hydroxy, alkoxy, acyl, or alkylsulfonyl; and all other groups areas defined in the Summary of the Invention for a Compound of Formula (I)or in any embodiments described herein. In some or any embodiments,provided is a Compound of Formula (I), (Ia), (Id), (Ie), (If), (Ig),(Ih), (Ij), (Ik), (Im), (100), (Ia-1), (Id-1), (Ie-1), (If-1), (Ig-1),(Ih-1), (Ij-1), (Ik-1), or (Im-1) where R^(1b) and additionallyoptionally substituted with 1 R^(1a); and R^(1b) is alkyl, haloalkyl,cycloalkylalkyl, or heterocycloalkylalkyl where the heterocycloalkyl issubstituted with alkyl; and all other groups are as defined in theSummary of the Invention for a Compound of Formula (I) or in anyembodiments described herein.

In some or any embodiments, the Compound of Formula (I), (100), (Ia), or(Ia-1) is that where R¹ is phenyl, pyridinonyl, or pyridinyl; where thephenyl and pyridinyl rings are optionally substituted with 1 or 2 R^(1a)and where the pyridinonyl is substituted on the nitrogen with R^(1b) andis additionally optionally substituted with 1 R^(1a); R³ and R⁴ arehydrogen; R² is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein.

In some or any embodiments, the Compound of Formula (I), (100), (Ia), or(Ia-1) is that where R¹ is phenyl, pyridinonyl, or pyridinyl; where thephenyl and pyridinyl rings are optionally substituted with 1 or 2 R^(1a)and where the pyridinonyl is substituted on the nitrogen with R^(1b) andis additionally optionally substituted with 1 R^(1a); R³ and R⁴ arehydrogen; R² is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein.

A Compound according to Formula (Ia-1):

where R¹, R², R³, R⁴, and all other groups are as defined in the Summaryof the Invention for a Compound of Formula (I) or in any embodimentsdescribed herein; or a pharmaceutically acceptable salt thereof. In someor an embodiments, the Compound of Formula (Ia-1) is that where R² is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (Ia-1) is that where R²is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (Ia-1) is that where R³and R⁴ are hydrogen.

In some or any embodiments, the Compound is according to Formula (Ib-1):

where R^(1a), R², R³, R⁴, and all other groups are as defined in theSummary of the Invention for a Compound of Formula (I) or in anyembodiments described herein; or a pharmaceutically acceptable saltthereof. In some or any embodiments, the Compound of Formula (Ib-1) isthat where R² is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (Ib-1) is that where R²is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (Ib-1) is that where R³and R⁴ are hydrogen.

In some or any embodiments, the Compound is according to Formula (Ic-1):

where R^(1a), R², R³, R⁴, and all other groups are as defined in theSummary of the Invention for a Compound of Formula (I) or in anyembodiments described herein; or a pharmaceutically acceptable saltthereof. In some or any embodiments, the Compound of Formula (Ic-1) isthat where R² is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (Ic-1) is that where R²is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (Ic-1) is that where R³and R⁴ are hydrogen.

In some or any embodiments, the Compound is according to Formula (Id-1):

where R^(1a), R^(1b), R², R³, R⁴, and all other groups are as defined inthe Summary of the Invention for a Compound of Formula (I) or in anyembodiments described herein; or a pharmaceutically acceptable saltthereof. In some or any embodiments, the Compound of Formula (Id-1) isthat where R² is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or an embodiments, the Compound of Formula (Id-1) is that where R²is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (Id-1) is that where R²is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (Id-1) is that where R²is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (Id-1) is that where R²is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (Id-1) is that where R²is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (Id-1) is that where R³and R⁴ are hydrogen.

In some or any embodiments, the Compound is according to Formula (Ie-1):

where R¹, R^(2a), R^(2b), R³, R⁴, and all other groups are as defined inthe Summary of the Invention for a Compound of Formula (I) or in anyembodiments described herein; or a pharmaceutically acceptable saltthereof. In some or any embodiments, the Compound of Formula (Ie-1) isthat wherein R¹ is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (Ie-1) is that whereinR¹ is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (Ie-1) is that where R³and R⁴ are hydrogen. In some or any embodiments, the Compound of Formula(Ie-1) is that where one R^(2b) is present.

In some or any embodiments, the Compound is according to Formula (If-1):

where R¹, R^(2a), R^(2b), R³, R⁴, and all other groups are as defined inthe Summary of the Invention for a Compound of Formula (I) or in anyembodiments described herein; or a pharmaceutically acceptable saltthereof. In some or any embodiments, the Compound of Formula (If-1) isthat wherein R¹ is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (If-1) is that whereinR¹ is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (If-1) is that where R³and R⁴ are hydrogen. In some or any embodiments, the Compound of Formula(If-1) is that where one R^(2b) is present.

In some or any embodiments, the Compound is according to Formula (Ig-1):

where R¹, R^(2a), R^(2b), R³, R⁴, and all other groups are as defined inthe Summary of the Invention for a Compound of Formula (I) or in anyembodiments described herein; or a pharmaceutically acceptable saltthereof. In some or any embodiments, the Compound of Formula (Ig-1) isthat wherein R¹ is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (Ig-1) is that where R³and R⁴ are hydrogen. In some or any embodiments, the Compound of Formula(Ig-1) is that where one R^(2b) is present.

In some or any embodiments, the Compound is according to Formula (Ih-1):

where R¹, R^(2a), R², R³, R⁴, and all other groups are as defined in theSummary of the Invention for a Compound of Formula (I) or in anyembodiments described herein; or a pharmaceutically acceptable saltthereof. In some or any embodiments, the Compound of Formula (Ih-1) isthat wherein R¹ is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (Ih-1) is that where R³and R⁴ are hydrogen. In some or any embodiments, the Compound of Formula(Ih-1) is that where one R^(2b) is present.

In some or any embodiments, the Compound is according to Formula (Ij-1):

where R¹, R^(2a), R², R³, R⁴, and all other groups are as defined in theSummary of the Invention for a Compound of Formula (I) or in anyembodiments described herein; or a pharmaceutically acceptable saltthereof. In some or any embodiments, the Compound of Formula (Ij-1) isthat wherein R¹ is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (Ij-1) is that where R³and R⁴ are hydrogen. In some or any embodiments, the Compound of Formula(Ij-1) is that where one R^(2b) is present.

In some or any embodiments, the Compound is according to Formula (Ik-1):

where R¹, R^(2a), R^(2b), R³, R⁴, and all other groups are as defined inthe Summary of the Invention for a Compound of Formula (I) or in anyembodiments described herein; or a pharmaceutically acceptable saltthereof. In some or any embodiments, the Compound of Formula (Ik-1) isthat wherein R¹ is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (Ik-1) is that where R³and R⁴ are hydrogen. In some or any embodiments, the Compound of Formula(Ik-1) is that where one R^(2b) is present.

In some or any embodiments, the Compound is according to Formula (Im-1):

where R¹, R^(2a), R^(2b), R³, R⁴, and all other groups are as defined inthe Summary of the Invention for a Compound of Formula (I) or in anyembodiments described herein; or a pharmaceutically acceptable saltthereof. In some or any embodiments, the Compound of Formula (Im-1) isthat wherein R¹ is

and all other groups are as defined in the Summary of the Invention fora Compound of Formula (I) or in any embodiments described herein. Insome or any embodiments, the Compound of Formula (Im-1) is that where R³and R⁴ are hydrogen. In some or any embodiments, the Compound of Formula(Im-1) is that where one R^(2b) is present. In some or any embodiments,the Compound of Formula (Im-1) is that where no R^(2b) is present.

In some or any embodiments, the Compound of Formula (II) or (200) is not

In some or any embodiments, the Compound (e.g., of Formula (II) and(200), and any embodiments thereof) is not a pharmaceutically acceptablesalt of one of the specific compounds in this paragraph.

In some or any embodiments, provided is a Compound according to any ofthe following formula:

In some embodiments, provided herein are:

-   -   (a) compounds as described herein, e.g., of Formula (I)-(Im),        (100), (200), (I)-(Im), and (Ia-1)-(Im-1) and Examples 1-130 and        Embodiment A, and pharmaceutically acceptable salts and        compositions thereof,    -   (b) compounds as described herein, e.g., of Formula (I)-(Im),        (100), (200), (I)-(Im), and (Ia-1)-(Im-1) and Examples 1-130 and        Embodiment A, and pharmaceutically acceptable salts and        compositions thereof for use in the treatment of a condition,        disease, or disorder associated with abnormal activation of the        SREBP pathway;    -   (c) processes for the preparation of compounds as described        herein, e.g., of Formula (I)-(Im), (100), (200), (I)-(Im), and        (Ia-1)-(Im-1) and Examples 1-130 and Embodiment A, as described        in more detail elsewhere herein;    -   (d) pharmaceutical formulations comprising a compound as        described herein, e.g., of Formula (I)-(Im), (100), (200),        (I)-(Im), and (Ia-1)-(Im-1) and Examples 1-130 and Embodiment A,        or a pharmaceutically acceptable salt thereof together with a        pharmaceutically acceptable carrier;    -   (e) a method for the treatment of a condition, disease, or        disorder associated with abnormal activation of the SREBP        pathway in a subject that includes the administration of an        effective treatment amount of a compound as described herein,        e.g., of Formula (I)-(Im), (100), (200), (I)-(Im), and        (Ia-1)-(Im-1) and Examples 1-130 and Embodiment A, its        pharmaceutically acceptable salt or composition;    -   (f) pharmaceutical formulations comprising a compound as        described herein, e.g., of Formula (I)-(Im), (100), (200),        (I)-(Im), and (Ia-1)-(Im-1) and Examples 1-130 and Embodiment A,        or a pharmaceutically acceptable salt thereof together with one        or more other effective agents for treating a condition,        disease, or disorder associated with abnormal activation of the        SREBP pathway, optionally in a pharmaceutically acceptable        carrier; or    -   (g) a method for the treatment of a condition, disease, or        disorder associated with abnormal activation of the SREBP        pathway in a subject that includes the administration of an        effective treatment amount of a compound as described herein,        e.g., of Formula (I)-(Im), (100), (200), (I)-(Im), and        (Ia-1)-(Im-1) and Examples 1-130 and Embodiment A, its        pharmaceutically acceptable salt or composition in combination        and/or alternation with one or more agent for the treatment of a        condition, disease, or disorder associated with abnormal        activation of the SREBP pathway.

Optically Active Compounds

It is appreciated that compounds provided herein may have one or morechiral centers and may exist in and be isolated in optically active andracemic forms. It is to be understood that any racemic,optically-active, diastereomeric, tautomeric, or stereoisomeric form, ormixtures thereof, of a compound provided herein, which possess theuseful properties described herein is within the scope of the invention.It being well known in the art how to prepare optically active forms(e.g., in certain embodiments, by resolution of the racemic form byrecrystallization techniques, by synthesis from optically-activestarting materials, by chiral synthesis, or by chromatographicseparation using a chiral stationary phase).

In certain embodiments, methods to obtain optically active materials areknown in the art, and include at least the following.

-   -   i) physical separation of crystals—a technique whereby        macroscopic crystals of the individual stereoisomers are        manually separated. This technique can be used if crystals of        the separate stereoisomers exist, i.e., the material is a        conglomerate, and the crystals are visually distinct;    -   ii) simultaneous crystallization—a technique whereby the        individual stereoisomers are separately crystallized from a        solution of the racemate, possible only if the latter is a        conglomerate in the solid state;    -   iii) enzymatic resolutions—a technique whereby partial or        complete separation of a racemate by virtue of differing rates        of reaction for the stereoisomers with an enzyme;    -   iv) enzymatic asymmetric synthesis—a synthetic technique whereby        at least one step of the synthesis uses an enzymatic reaction to        obtain an stereoisomerically pure or enriched synthetic        precursor of the desired stereoisomer;    -   v) chemical asymmetric synthesis—a synthetic technique whereby        the desired stereoisomer is synthesized from an achiral        precursor under conditions that produce asymmetry (i.e.,        chirality) in the product, which may be achieved using chiral        catalysts or chiral auxiliaries;    -   vi) diastereomer separations—a technique whereby a racemic        compound is reacted with an enantiomerically pure reagent (the        chiral auxiliary) that converts the individual enantiomers to        diastereomers. The resulting diastereomers are then separated by        chromatography or crystallization by virtue of their now more        distinct structural differences and the chiral auxiliary is        later removed to obtain the desired enantiomer;    -   vii) first- and second-order asymmetric transformations—a        technique whereby diastereomers from the racemate equilibrate to        yield a preponderance in solution of the diastereomer from the        desired enantiomer or where preferential crystallization of the        diastereomer from the desired enantiomer perturbs the        equilibrium such that eventually in principle all the material        is converted to the crystalline diastereomer from the desired        enantiomer. The desired enantiomer is then released from the        diastereomer;    -   viii) kinetic resolutions—this technique refers to the        achievement of partial or complete resolution of a racemate (or        of a further resolution of a partially resolved compound) by        virtue of unequal reaction rates of the stereoisomers with a        chiral, non-racemic reagent or catalyst under kinetic        conditions;    -   ix) stereospecific synthesis from non-racemic precursors—a        synthetic technique whereby the desired stereoisomer is obtained        from non-chiral starting materials and where the stereochemical        integrity is not or is only minimally compromised over the        course of the synthesis;    -   x) chiral liquid chromatography—a technique whereby the        stereoisomers of a racemate are separated in a liquid mobile        phase by virtue of their differing interactions with a        stationary phase. The stationary phase can be made of chiral        material or the mobile phase can contain an additional chiral        material to provoke the differing interactions;    -   xi) chiral gas chromatography—a technique whereby the racemate        is volatilized and stereoisomers are separated by virtue of        their differing interactions in the gaseous mobile phase with a        column containing a fixed non-racemic chiral adsorbent phase;    -   xii) extraction with chiral solvents—a technique whereby the        stereoisomers are separated by virtue of preferential        dissolution of one stereoisomer into a particular chiral        solvent;    -   xiii) transport across chiral membranes—a technique whereby a        racemate is placed in contact with a thin membrane barrier. The        barrier typically separates two miscible fluids, one containing        the racemate, and a driving force such as concentration or        pressure differential causes preferential transport across the        membrane barrier. Separation occurs as a result of the        non-racemic chiral nature of the membrane which allows only one        stereoisomer of the racemate to pass through.

Isotopically Enriched Compounds

Also provided herein are isotopically enriched compounds, including butnot limited to isotopically enriched di-substituted pyrazoles.

Isotopic enrichment (in certain embodiments, deuteration) ofpharmaceuticals to improve pharmacokinetics (“PK”), pharmacodynamics(“PD”), and toxicity profiles, has been demonstrated previously withsome classes of drugs. See, for example, Lijinsky et al. Food Cosmet.Toxicol., 20: 393 (1982); Lijinsky et al. J. Nat. Cancer Inst., 69: 1127(1982); Mangold et al. Mutation Res. 308: 33 (1994); Gordon et al. DrugMetab. Dispos., 15: 589 (1987); Zello et. al. Metabolism, 43: 487(1994); Gately et. al. J. Nucl. Med., 27: 388 (1986); Wade D, Chem.Biol. Interact. 117: 191 (1999).

Isotopic enrichment of a drug can be used, in certain embodiments, to(1) reduce or eliminate unwanted metabolites, (2) increase the half-lifeof the parent drug, (3) decrease the number of doses needed to achieve adesired effect, (4) decrease the amount of a dose necessary to achieve adesired effect, (5) increase the formation of active metabolites, if anyare formed, and/or (6) decrease the production of deleteriousmetabolites in specific tissues and/or create a more effective drugand/or a safer drug for combination therapy, whether the combinationtherapy is intentional or not.

Replacement of an atom for one of its isotopes often will result in achange in the reaction rate of a chemical reaction. This phenomenon isknown as the Kinetic Isotope Effect (“KIE”). For example, if a C—H bondis broken during a rate-determining step in a chemical reaction (i.e.,the step with the highest transition state energy), substitution of adeuterium for that hydrogen will cause a decrease in the reaction rateand the process will slow down. This phenomenon is known as theDeuterium Kinetic Isotope Effect (“DKIE”). See, e.g., Foster et al. Adv.Drug Res., vol. 14, pp. 1-36 (1985); Kushner et al. Can. J. Physiol.Pharmacol., vol. 77, pp. 79-88 (1999).

The magnitude of the DKIE can be expressed as the ratio between therates of a given reaction in which a C—H bond is broken, and the samereaction where deuterium is substituted for hydrogen. The DKIE can rangefrom about 1 (no isotope effect) to very large numbers, such as 50 ormore, meaning that the reaction can be fifty, or more, times slower whendeuterium is substituted for hydrogen. High DKIE values may be due inpart to a phenomenon known as tunneling, which is a consequence of theuncertainty principle. Tunneling is ascribed to the small mass of ahydrogen atom, and occurs because transition states involving a protoncan sometimes form in the absence of the required activation energy.Because deuterium has more mass than hydrogen, it statistically has amuch lower probability of undergoing this phenomenon.

Tritium (“T”) is a radioactive isotope of hydrogen, used in research,fusion reactors, neutron generators and radiopharmaceuticals. Tritium isa hydrogen atom that has 2 neutrons in the nucleus and has an atomicweight close to 3. It occurs naturally in the environment in very lowconcentrations, most commonly found as T20. Tritium decays slowly(half-life=12.3 years) and emits a low energy beta particle that cannotpenetrate the outer layer of human skin. Internal exposure is the mainhazard associated with this isotope, yet it must be ingested in largeamounts to pose a significant health risk. As compared with deuterium, alesser amount of tritium must be consumed before it reaches a hazardouslevel. Substitution of tritium (“T”) for hydrogen results in yet astronger bond than deuterium and gives numerically larger isotopeeffects. Similarly, substitution of isotopes for other elements,including, but not limited to, ¹³C or ¹⁴C for carbon, ³³S, ³⁴S, or ³⁶Sfor sulfur, ¹⁵N for nitrogen, and ¹⁷O or ¹⁸O for oxygen, may lead to asimilar kinetic isotope effect.

For example, the DKIE was used to decrease the hepatotoxicity ofhalothane by presumably limiting the production of reactive species suchas trifluoroacetyl chloride. However, this method may not be applicableto all drug classes. For example, deuterium incorporation can lead tometabolic switching. The concept of metabolic switching asserts thatxenogens, when sequestered by Phase I enzymes, may bind transiently andre-bind in a variety of conformations prior to the chemical reaction(e.g., oxidation). This hypothesis is supported by the relatively vastsize of binding pockets in many Phase I enzymes and the promiscuousnature of many metabolic reactions. Metabolic switching can potentiallylead to different proportions of known metabolites as well as altogethernew metabolites. This new metabolic profile may impart more or lesstoxicity.

The animal body expresses a variety of enzymes for the purpose ofeliminating foreign substances, such as therapeutic agents, from itscirculation system. In certain embodiments, such enzymes include thecytochrome P450 enzymes (“CYPs”), esterases, proteases, reductases,dehydrogenases, and monoamine oxidases, to react with and convert theseforeign substances to more polar intermediates or metabolites for renalexcretion. Some of the most common metabolic reactions of pharmaceuticalcompounds involve the oxidation of a carbon-hydrogen (C—H) bond toeither a carbon-oxygen (C—O) or carbon-carbon (C—C) pi-bond. Theresultant metabolites may be stable or unstable under physiologicalconditions, and can have substantially different pharmacokinetic,pharmacodynamic, and acute and long-term toxicity profiles relative tothe parent compounds. For many drugs, such oxidations are rapid. Thesedrugs therefore often require the administration of multiple or highdaily doses.

Therefore, isotopic enrichment at certain positions of a compoundprovided herein will produce a detectable KIE that will affect thepharmacokinetic, pharmacologic, and/or toxicological profiles of acompound provided herein in comparison with a similar compound having anatural isotopic composition.

Preparation of Compounds

The compounds provided herein can be prepared, isolated or obtained byany method apparent to those of skill in the art. Compounds providedherein can be prepared according to the Exemplary Preparation Schemesprovided below. Reaction conditions, steps and reactants not provided inthe Exemplary Preparation Schemes would be apparent to, and known by,those skilled in the art.

Additional steps and reagents not provided in the Exemplary PreparationScheme would be known to those of skill in the art. Exemplary methods ofpreparation are described in detail in the Examples herein.

Pharmaceutical Compositions and Methods of Administration

The compounds provided herein can be formulated into pharmaceuticalcompositions using methods available in the art and those disclosedherein. Any of the compounds disclosed herein can be provided in theappropriate pharmaceutical composition and be administered by a suitableroute of administration.

The methods provided herein encompass administering pharmaceuticalcompositions containing at least one compound as described herein,including a compound of Formula (I)-(Im) (100), (200), (I)-(Im), and(Ia-1)-(Im-1) and 1-130 and Embodiment A, if appropriate in a salt form,either used alone or in the form of a combination with one or morecompatible and pharmaceutically acceptable carriers, such as diluents oradjuvants, or with another agent for the treatment of a condition,disease, or disorder associated with abnormal activation of the SREBPpathway.

In certain embodiments, the second agent can be formulated or packagedwith the compound provided herein. Of course, the second agent will onlybe formulated with the compound provided herein when, according to thejudgment of those of skill in the art, such co-formulation should notinterfere with the activity of either agent or the method ofadministration. In certain embodiments, the compound provided herein andthe second agent are formulated separately. They can be packagedtogether, or packaged separately, for the convenience of thepractitioner of skill in the art.

In clinical practice the active agents provided herein may beadministered by any conventional route, in particular orally,parenterally, rectally or by inhalation (e.g. in the form of aerosols).In certain embodiments, the compound provided herein is administeredorally.

Use may be made, as solid compositions for oral administration, oftablets, pills, hard gelatin capsules, powders or granules. In thesecompositions, the active product is mixed with one or more inertdiluents or adjuvants, such as sucrose, lactose or starch.

These compositions can comprise substances other than diluents, forexample a lubricant, such as magnesium stearate, or a coating intendedfor controlled release.

Use may be made, as liquid compositions for oral administration, ofsolutions which are pharmaceutically acceptable, suspensions, emulsions,syrups and elixirs containing inert diluents, such as water or liquidparaffin. These compositions can also comprise substances other thandiluents, in certain embodiments, wetting, sweetening or flavoringproducts.

The compositions for parenteral administration can be emulsions orsterile solutions. Use may be made, as solvent or vehicle, of propyleneglycol, a polyethylene glycol, vegetable oils, in particular olive oil,or injectable organic esters, in certain embodiments, ethyl oleate.These compositions can also contain adjuvants, in particular wetting,isotonizing, emulsifying, dispersing and stabilizing agents.Sterilization can be carried out in several ways, in certainembodiments, using a bacteriological filter, by radiation or by heating.They can also be prepared in the form of sterile solid compositionswhich can be dissolved at the time of use in sterile water or any otherinjectable sterile medium.

The compositions for rectal administration are suppositories or rectalcapsules which contain, in addition to the active principle, excipientssuch as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

The compositions can also be aerosols. For use in the form of liquidaerosols, the compositions can be stable sterile solutions or solidcompositions dissolved at the time of use in a pyrogenic sterile water,in saline or any other pharmaceutically acceptable vehicle. For use inthe form of dry aerosols intended to be directly inhaled, the activeprinciple is finely divided and combined with a water-soluble soliddiluent or vehicle, in certain embodiments, dextran, mannitol orlactose.

In certain embodiments, a composition provided herein is apharmaceutical composition or a single unit dosage form. Pharmaceuticalcompositions and single unit dosage forms provided herein comprise aprophylactically or therapeutically effective amount of one or moreprophylactic or therapeutic agents (e.g., a compound provided herein, orother prophylactic or therapeutic agent), and a typically one or morepharmaceutically acceptable carriers. In a specific embodiment and inthis context, the term “pharmaceutically acceptable” means approved by aregulatory agency of the Federal or a state government or listed in theU.S. Pharmacopeia or other generally recognized pharmacopeia for use inanimals, and more particularly in humans. The term “carrier” includes adiluent, adjuvant (e.g., Freund's adjuvant (complete and incomplete)),excipient, or vehicle with which the therapeutic is administered. Anyembodiment described for “excipient”. Such pharmaceutical carriers canbe sterile liquids, such as water and oils, including those ofpetroleum, animal, vegetable or synthetic origin, such as peanut oil,soybean oil, mineral oil, sesame oil and the like. Water can be used asa carrier when the pharmaceutical composition is administeredintravenously. Saline solutions and aqueous dextrose and glycerolsolutions can also be employed as liquid carriers, particularly forinjectable solutions. Examples of suitable pharmaceutical carriers aredescribed in Remington: The Science and Practice of Pharmacy;Pharmaceutical Press; 22 edition (Sep. 15, 2012).

Typical pharmaceutical compositions and dosage forms comprise one ormore excipients. Suitable excipients are well-known to those skilled inthe art of pharmacy, and in certain embodiments, suitable excipientsinclude starch, glucose, lactose, sucrose, gelatin, malt, rice, flour,chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodiumchloride, dried skim milk, glycerol, propylene, glycol, water, ethanoland the like. Whether a particular excipient is suitable forincorporation into a pharmaceutical composition or dosage form dependson a variety of factors well known in the art including, but not limitedto, the way in which the dosage form will be administered to a subjectand the specific active ingredients in the dosage form. The compositionor single unit dosage form, if desired, can also contain minor amountsof wetting or emulsifying agents, or pH buffering agents.

Lactose free compositions provided herein can comprise excipients thatare well known in the art and are listed, in certain embodiments, in theU.S. Pharmacopeia (USP 36-NF 31 S2). In general, lactose freecompositions comprise an active ingredient, a binder/filler, and alubricant in pharmaceutically compatible and pharmaceutically acceptableamounts. Exemplary lactose free dosage forms comprise an activeingredient, microcrystalline cellulose, pre gelatinized starch, andmagnesium stearate.

Further encompassed herein are anhydrous pharmaceutical compositions anddosage forms comprising active ingredients, since water can facilitatethe degradation of some compounds. For example, the addition of water(e.g., 5%) is widely accepted in the pharmaceutical arts as a means ofsimulating long term storage in order to determine characteristics suchas shelf life or the stability of formulations over time. See, e.g.,Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed.,Marcel Dekker, New York, 1995, pp. 379 80. In effect, water and heataccelerate the decomposition of some compounds. Thus, the effect ofwater on a formulation can be of great significance since moistureand/or humidity are commonly encountered during manufacture, handling,packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms provided hereincan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. Pharmaceutical compositionsand dosage forms that comprise lactose and at least one activeingredient that comprises a primary or secondary amine can be anhydrousif substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions can be packaged using materials known to prevent exposureto water such that they can be included in suitable formulary kits. Incertain embodiments, suitable packaging include, but are not limited to,hermetically sealed foils, plastics, unit dose containers (e.g., vials),blister packs, and strip packs.

Further provided are pharmaceutical compositions and dosage forms thatcomprise one or more compounds that reduce the rate by which an activeingredient will decompose. Such compounds, which are referred to hereinas “stabilizers,” include, but are not limited to, antioxidants such asascorbic acid, pH buffers, or salt buffers.

The pharmaceutical compositions and single unit dosage forms can takethe form of solutions, suspensions, emulsion, tablets, pills, capsules,powders, sustained-release formulations and the like. Oral formulationcan include standard carriers such as pharmaceutical grades of mannitol,lactose, starch, magnesium stearate, sodium saccharine, cellulose,magnesium carbonate, etc. Such compositions and dosage forms willcontain a prophylactically or therapeutically effective amount of aprophylactic or therapeutic agent, in certain embodiments, in purifiedform, together with a suitable amount of carrier so as to provide theform for proper administration to the subject. The formulation shouldsuit the mode of administration. In a certain embodiment, thepharmaceutical compositions or single unit dosage forms are sterile andin suitable form for administration to a subject, in certainembodiments, an animal subject, such as a mammalian subject, in certainembodiments, a human subject.

A pharmaceutical composition is formulated to be compatible with itsintended route of administration. In certain embodiments, routes ofadministration include, but are not limited to, parenteral, e.g.,intravenous, intradermal, subcutaneous, intramuscular, subcutaneous,oral, buccal, sublingual, inhalation, intranasal, transdermal, topical,transmucosal, intra-tumoral, intra-synovial and rectal administration.In a specific embodiment, the composition is formulated in accordancewith routine procedures as a pharmaceutical composition adapted forintravenous, subcutaneous, intramuscular, oral, intranasal or topicaladministration to human beings. In an embodiment, a pharmaceuticalcomposition is formulated in accordance with routine procedures forsubcutaneous administration to human beings. Typically, compositions forintravenous administration are solutions in sterile isotonic aqueousbuffer. Where necessary, the composition may also include a solubilizingagent and a local anesthetic such as lignocamne to ease pain at the siteof the injection.

In certain embodiments, dosage forms include, but are not limited to:tablets; caplets; capsules, such as soft elastic gelatin capsules;cachets; troches; lozenges; dispersions; suppositories; ointments;cataplasms (poultices); pastes; powders; dressings; creams; plasters;solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels;liquid dosage forms suitable for oral or mucosal administration to asubject, including suspensions (e.g., aqueous or non-aqueous liquidsuspensions, oil in water emulsions, or a water in oil liquidemulsions), solutions, and elixirs; liquid dosage forms suitable forparenteral administration to a subject; and sterile solids (e.g.,crystalline or amorphous solids) that can be reconstituted to provideliquid dosage forms suitable for parenteral administration to a subject.

The composition, shape, and type of dosage forms provided herein willtypically vary depending on their use. In certain embodiments, a dosageform used in the initial treatment of viral infection may contain largeramounts of one or more of the active ingredients it comprises than adosage form used in the maintenance treatment of the same infection.Similarly, a parenteral dosage form may contain smaller amounts of oneor more of the active ingredients it comprises than an oral dosage formused to treat the same disease or disorder. These and other ways inwhich specific dosage forms encompassed herein will vary from oneanother will be readily apparent to those skilled in the art. See, e.g.,Remington: The Science and Practice of Pharmacy; Pharmaceutical Press;22 edition (Sep. 15, 2012).

Generally, the ingredients of compositions are supplied eitherseparately or mixed together in unit dosage form, in certainembodiments, as a dry lyophilized powder or water free concentrate in ahermetically sealed container such as an ampoule or sachet indicatingthe quantity of active agent. Where the composition is to beadministered by infusion, it can be dispensed with an infusion bottlecontaining sterile pharmaceutical grade water or saline. Where thecomposition is administered by injection, an ampoule of sterile waterfor injection or saline can be provided so that the ingredients may bemixed prior to administration.

Typical dosage forms comprise a compound provided herein, or apharmaceutically acceptable salt, solvate or hydrate thereof lie withinthe range of from about 0.1 mg to about 1000 mg per day, given as asingle once-a-day dose in the morning or as divided doses throughout theday taken with food. Particular dosage forms can have about 0.1, 0.2,0.3, 0.4, 0.5, 1.0, 2.0, 2.5, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 100,200, 250, 500 or 1000 mg of the active compound.

Oral Dosage Forms

Pharmaceutical compositions that are suitable for oral administrationcan be presented as discrete dosage forms, such as, but are not limitedto, tablets (e.g., chewable tablets), caplets, capsules, and liquids(e.g., flavored syrups). Such dosage forms contain predetermined amountsof active ingredients, and may be prepared by methods of pharmacy wellknown to those skilled in the art. See generally, Remington: The Scienceand Practice of Pharmacy; Pharmaceutical Press; 22 edition (Sep. 15,2012).

In certain embodiments, the oral dosage forms are solid and preparedunder anhydrous conditions with anhydrous ingredients, as described indetail herein. However, the scope of the compositions provided hereinextends beyond anhydrous, solid oral dosage forms. As such, furtherforms are described herein.

Typical oral dosage forms are prepared by combining the activeingredient(s) in an intimate admixture with at least one excipientaccording to conventional pharmaceutical compounding techniques.Excipients can take a wide variety of forms depending on the form ofpreparation desired for administration. In certain embodiments,excipients suitable for use in oral liquid or aerosol dosage formsinclude, but are not limited to, water, glycols, oils, alcohols,flavoring agents, preservatives, and coloring agents. In certainembodiments, excipients suitable for use in solid oral dosage forms(e.g., powders, tablets, capsules, and caplets) include, but are notlimited to, starches, sugars, micro crystalline cellulose, diluents,granulating agents, lubricants, binders, and disintegrating agents.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit forms, in which case solidexcipients are employed. If desired, tablets can be coated by standardaqueous or non-aqueous techniques. Such dosage forms can be prepared byany of the methods of pharmacy. In general, pharmaceutical compositionsand dosage forms are prepared by uniformly and intimately admixing theactive ingredients with liquid carriers, finely divided solid carriers,or both, and then shaping the product into the desired presentation ifnecessary.

In certain embodiments, a tablet can be prepared by compression ormolding. Compressed tablets can be prepared by compressing in a suitablemachine the active ingredients in a free flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

In certain embodiments, excipients that can be used in oral dosage formsinclude, but are not limited to, binders, fillers, disintegrants, andlubricants. Binders suitable for use in pharmaceutical compositions anddosage forms include, but are not limited to, corn starch, potatostarch, or other starches, gelatin, natural and synthetic gums such asacacia, sodium alginate, alginic acid, other alginates, powderedtragacanth, guar gum, cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, carboxymethyl cellulose calcium, sodiumcarboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos. 2208,2906, 2910), microcrystalline cellulose, and mixtures thereof.

In certain embodiments, fillers suitable for use in the pharmaceuticalcompositions and dosage forms disclosed herein include, but are notlimited to, talc, calcium carbonate (e.g., granules or powder),microcrystalline cellulose, powdered cellulose, dextrates, kaolin,mannitol, silicic acid, sorbitol, starch, pre gelatinized starch, andmixtures thereof. The binder or filler in pharmaceutical compositions istypically present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

In certain embodiments, suitable forms of microcrystalline celluloseinclude, but are not limited to, the materials sold as AVICEL PH 101,AVICEL PH 103 AVICEL RC 581, AVICEL PH 105 (available from FMCCorporation, American Viscose Division, Avicel Sales, Marcus Hook, Pa.),and mixtures thereof. A specific binder is a mixture of microcrystallinecellulose and sodium carboxymethyl cellulose sold as AVICEL RC 581.Suitable anhydrous or low moisture excipients or additives includeAVICEL PH 103™ and Starch 1500 LM.

Disintegrants are used in the compositions to provide tablets thatdisintegrate when exposed to an aqueous environment. Tablets thatcontain too much disintegrant may disintegrate in storage, while thosethat contain too little may not disintegrate at a desired rate or underthe desired conditions. Thus, a sufficient amount of disintegrant thatis neither too much nor too little to detrimentally alter the release ofthe active ingredients should be used to form solid oral dosage forms.The amount of disintegrant used varies based upon the type offormulation, and is readily discernible to those of ordinary skill inthe art. Typical pharmaceutical compositions comprise from about 0.5 toabout 15 weight percent of disintegrant, specifically from about 1 toabout 5 weight percent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosageforms include, but are not limited to, agar, alginic acid, calciumcarbonate, microcrystalline cellulose, croscarmellose sodium,crospovidone, polacrilin potassium, sodium starch glycolate, potato ortapioca starch, pre gelatinized starch, other starches, clays, otheralgins, other celluloses, gums, and mixtures thereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms include, but are not limited to, calcium stearate, magnesiumstearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol,polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate,talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil,sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zincstearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.Additional lubricants include, in certain embodiments, a syloid silicagel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore, Md.), acoagulated aerosol of synthetic silica (marketed by Degussa Co. ofPlano, Tex.), CAB O SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. If used at all,lubricants are typically used in an amount of less than about 1 weightpercent of the pharmaceutical compositions or dosage forms into whichthey are incorporated.

Delayed Release Dosage Forms

Active ingredients such as the compounds provided herein can beadministered by controlled release means or by delivery devices that arewell known to those of ordinary skill in the art. In certainembodiments, but are not limited to, those described in U.S. Pat. Nos.3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533;5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556;5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356; 5,972,891;5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350;6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548;6,613,358; and 6,699,500; each of which is incorporated herein byreference in its entirety. Such dosage forms can be used to provide slowor controlled release of one or more active ingredients using, incertain embodiments, hydropropylmethyl cellulose, other polymermatrices, gels, permeable membranes, osmotic systems, multilayercoatings, microparticles, liposomes, microspheres, or a combinationthereof to provide the desired release profile in varying proportions.Suitable controlled release formulations known to those of ordinaryskill in the art, including those described herein, can be readilyselected for use with the active ingredients provided herein. Thusencompassed herein are single unit dosage forms suitable for oraladministration such as, but not limited to, tablets, capsules, gel caps,and caplets that are adapted for controlled release.

All controlled release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledcounterparts. Ideally, the use of an optimally designed controlledrelease preparation in medical treatment is characterized by a minimumof drug substance being employed to cure or control the condition,disease, or disorder in a minimum amount of time. Advantages ofcontrolled release formulations include extended activity of the drug,reduced dosage frequency, and increased subject compliance. In addition,controlled release formulations can be used to affect the time of onsetof action or other characteristics, such as blood levels of the drug,and can thus affect the occurrence of side (e.g., adverse) effects.

Most controlled release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release of otheramounts of drug to maintain this level of therapeutic or prophylacticeffect over an extended period of time. In order to maintain thisconstant level of drug in the body, the drug must be released from thedosage form at a rate that will replace the amount of drug beingmetabolized and excreted from the body. Controlled release of an activeingredient can be stimulated by various conditions including, but notlimited to, pH, temperature, enzymes, water, or other physiologicalconditions or compounds.

In certain embodiments, the drug may be administered using intravenousinfusion, an implantable osmotic pump, a transdermal patch, liposomes,or other modes of administration. In certain embodiments, a pump may beused (see, Sefton, CRC Crit. Ref Biomed. Eng. 14:201 (1987); Buchwald etal., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574(1989)). In another embodiment, polymeric materials can be used. In yetanother embodiment, a controlled release system can be placed in asubject at an appropriate site determined by a practitioner of skill,i.e., thus requiring only a fraction of the systemic dose (see, e.g.,Goodson, Medical Applications of Controlled Release, vol. 2, pp. 115-138(1984)). Other controlled release systems are discussed in the review byLanger (Science 249:1527-1533 (1990)). The active ingredient can bedispersed in a solid inner matrix, e.g., polymethylmethacrylate,polybutylmethacrylate, plasticized or unplasticized polyvinylchloride,plasticized nylon, plasticized polyethyleneterephthalate, naturalrubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene,ethylene-vinylacetate copolymers, silicone rubbers,polydimethylsiloxanes, silicone carbonate copolymers, hydrophilicpolymers such as hydrogels of esters of acrylic and methacrylic acid,collagen, cross-linked polyvinylalcohol and cross-linked partiallyhydrolyzed polyvinyl acetate, that is surrounded by an outer polymericmembrane, e.g., polyethylene, polypropylene, ethylene/propylenecopolymers, ethylene/ethyl acrylate copolymers, ethylene/vinylacetatecopolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber,chlorinated polyethylene, polyvinylchloride, vinylchloride copolymerswith vinyl acetate, vinylidene chloride, ethylene and propylene, ionomerpolyethylene terephthalate, butyl rubber epichlorohydrin rubbers,ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcoholterpolymer, and ethylene/vinyloxyethanol copolymer, that is insoluble inbody fluids. The active ingredient then diffuses through the outerpolymeric membrane in a release rate controlling step. The percentage ofactive ingredient in such parenteral compositions is highly dependent onthe specific nature thereof, as well as the needs of the subject.

Parenteral Dosage Forms

In certain embodiments, provided are parenteral dosage forms. Parenteraldosage forms can be administered to subjects by various routesincluding, but not limited to, subcutaneous, intravenous (includingbolus injection), intramuscular, and intra-arterial. Because theiradministration typically bypasses subjects' natural defenses againstcontaminants, parenteral dosage forms are typically, sterile or capableof being sterilized prior to administration to a subject. In certainembodiments, parenteral dosage forms include, but are not limited to,solutions ready for injection, dry products ready to be dissolved orsuspended in a pharmaceutically acceptable vehicle for injection,suspensions ready for injection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage formsare well known to those skilled in the art. In certain embodiments,suitable vehicles include, but are not limited to: Water for InjectionUSP; aqueous vehicles such as, but not limited to, Sodium ChlorideInjection, Ringer's Injection, Dextrose Injection, Dextrose and SodiumChloride Injection, and Lactated Ringer's Injection; water misciblevehicles such as, but not limited to, ethyl alcohol, polyethyleneglycol, and polypropylene glycol; and non-aqueous vehicles such as, butnot limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyloleate, isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms.

Transdermal, Topical & Mucosal Dosage Forms

Also provided are transdermal, topical, and mucosal dosage forms.Transdermal, topical, and mucosal dosage forms include, but are notlimited to, ophthalmic solutions, sprays, aerosols, creams, lotions,ointments, gels, solutions, emulsions, suspensions, or other forms knownto one of skill in the art. See, e.g., Remington: The Science andPractice of Pharmacy; Pharmaceutical Press; 22 edition (Sep. 15, 2012);and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger,Philadelphia (1985). Dosage forms suitable for treating mucosal tissueswithin the oral cavity can be formulated as mouthwashes or as oral gels.Further, transdermal dosage forms include “reservoir type” or “matrixtype” patches, which can be applied to the skin and worn for a specificperiod of time to permit the penetration of a desired amount of activeingredients.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide transdermal, topical, and mucosal dosageforms encompassed herein are well known to those skilled in thepharmaceutical arts, and depend on the particular tissue to which agiven pharmaceutical composition or dosage form will be applied. Withthat fact in mind, typical excipients include, but are not limited to,water, acetone, ethanol, ethylene glycol, propylene glycol, butane 1,3diol, isopropyl myristate, isopropyl palmitate, mineral oil, andmixtures thereof to form lotions, tinctures, creams, emulsions, gels orointments, which are nontoxic and pharmaceutically acceptable.Moisturizers or humectants can also be added to pharmaceuticalcompositions and dosage forms if desired. Examples of such additionalingredients are well known in the art. See, e.g., Remington: The Scienceand Practice of Pharmacy; Pharmaceutical Press; 22 edition (Sep. 15,2012).

Depending on the specific tissue to be treated, additional componentsmay be used prior to, in conjunction with, or subsequent to treatmentwith active ingredients provided. In certain embodiments, penetrationenhancers can be used to assist in delivering the active ingredients tothe tissue. Suitable penetration enhancers include, but are not limitedto: acetone; various alcohols such as ethanol, oleyl, andtetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethylacetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such aspolyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; andvarious water soluble or insoluble sugar esters such as Tween 80(polysorbate 80) and Span 60 (sorbitan monostearate).

The pH of a pharmaceutical composition or dosage form, or of the tissueto which the pharmaceutical composition or dosage form is applied, mayalso be adjusted to improve delivery of one or more active ingredients.Similarly, the polarity of a solvent carrier, its ionic strength, ortonicity can be adjusted to improve delivery. Compounds such asstearates can also be added to pharmaceutical compositions or dosageforms to advantageously alter the hydrophilicity or lipophilicity of oneor more active ingredients so as to improve delivery. In this regard,stearates can serve as a lipid vehicle for the formulation, as anemulsifying agent or surfactant, and as a delivery enhancing orpenetration enhancing agent. Different salts, hydrates or solvates ofthe active ingredients can be used to further adjust the properties ofthe resulting composition.

Dosage and Unit Dosage Forms

In human therapeutics, the doctor will determine the posology which heconsiders most appropriate according to a preventive or curativetreatment and according to the age, weight, stage of the infection andother factors specific to the subject to be treated. In certainembodiments, doses are from about 1 to about 1000 mg per day for anadult, or from about 5 to about 250 mg per day or from about 10 to 50 mgper day for an adult. In certain embodiments, doses are from about 5 toabout 400 mg per day or 25 to 200 mg per day per adult. In certainembodiments, dose rates of from about 50 to about 500 mg per day arealso contemplated.

In further aspects, provided are methods of treating a condition,disease, or disorder associated with abnormal activation of the SREBPpathway in a subject by administering, to a subject in need thereof, aneffective amount of a compound provided herein, or a pharmaceuticallyacceptable salt thereof. The amount of the compound or composition whichwill be effective in the treatment of a disorder or one or more symptomsthereof will vary with the nature and severity of the condition,disease, or disorder, and the route by which the active ingredient isadministered. The frequency and dosage will also vary according tofactors specific for each subject depending on the specific therapy(e.g., therapeutic or prophylactic agents) administered, the severity ofthe disorder, disease, or condition, the route of administration, aswell as age, body, weight, response, and the past medical history of thesubject. Effective doses may be extrapolated from dose-response curvesderived from in vitro or animal model test systems.

In certain embodiments, exemplary doses of a composition includemilligram or microgram amounts of the active compound per kilogram ofsubject or sample weight (e.g., about 10 micrograms per kilogram toabout 50 milligrams per kilogram, about 100 micrograms per kilogram toabout 25 milligrams per kilogram, or about 100 microgram per kilogram toabout 10 milligrams per kilogram). For compositions provided herein, incertain embodiments, the dosage administered to a subject is 0.140 mg/kgto 3 mg/kg of the subject's body weight, based on weight of the activecompound. In certain embodiments, the dosage administered to a subjectis between 0.20 mg/kg and 2.00 mg/kg, or between 0.30 mg/kg and 1.50mg/kg of the subject's body weight.

In certain embodiments, the recommended daily dose range of acomposition provided herein for the condition, disease, or disorderdescribed herein lie within the range of from about 0.1 mg to about 1000mg per day, given as a single once-a-day dose or as divided dosesthroughout a day. In certain embodiments, the daily dose is administeredtwice daily in equally divided doses. In certain embodiments, a dailydose range should be from about 10 mg to about 200 mg per day, in otherembodiments, between about 10 mg and about 150 mg per day, in furtherembodiments, between about 25 and about 100 mg per day. It may benecessary to use dosages of the active ingredient outside the rangesdisclosed herein in some cases, as will be apparent to those of ordinaryskill in the art. Furthermore, it is noted that the clinician ortreating physician will know how and when to interrupt, adjust, orterminate therapy in conjunction with subject response.

Different therapeutically effective amounts may be applicable fordifferent conditions, diseases, or disorders, as will be readily knownby those of ordinary skill in the art. Similarly, amounts sufficient toprevent, manage, treat or ameliorate such disorders, but insufficient tocause, or sufficient to reduce, adverse effects associated with thecomposition provided herein are also encompassed by the herein describeddosage amounts and dose frequency schedules. Further, when a subject isadministered multiple dosages of a composition provided herein, not allof the dosages need be the same. In certain embodiments, the dosageadministered to the subject may be increased to improve the prophylacticor therapeutic effect of the composition or it may be decreased toreduce one or more side effects that a particular subject isexperiencing.

In certain embodiments, the daily dosage of the composition providedherein, based on weight of the active compound, administered to prevent,treat, manage, or ameliorate a condition, disorder, disease, or one ormore symptoms thereof in a subject is about 1 mg/kg, about 5 mg/kg,about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg,about 60 mg/kg, about 70 mg/kg, about 80 mg/kg, about 90 mg/kg, about100 mg/kg, about 125 mg/kg, about 150 mg/kg, about 175 mg/kg, about 200mg/kg, about 225 mg/kg, about 250 mg/kg, about 275 mg/kg, about 300mg/kg, about 325 mg/kg, bout 350 mg/kg, about 375 mg/kg, about 400mg/kg, about 425 mg/kg, about 450 mg/kg, about 475 mg/kg, about 500mg/kg, or about 600 mg/kg. In certain embodiments, the daily dosage ofthe composition provided herein, based on weight of the active compound,administered to prevent, treat, manage, or ameliorate a condition,disorder, disease, or one or more symptoms thereof in a subject isbetween (inclusive) about 1-10 mg/kg, about 10 mg/kg, about 25-50 mg/kg,about 50-100 mg/kg, about 50-150 mg/kg, about 100-150 mg/kg, about100-200 mg/kg, about 150-200 mg/kg, about 150-250 mg/kg, about 250-300mg/kg, about 300-350 mg·kg, about 300-400 mg/kg, about 200-400 mg/kg,about 100-300 mg/kg, or about 400-500 mg/kg.

In certain embodiment, the twice daily dosage of the compositionprovided herein, based on weight of the active compound, administered toprevent, treat, manage, or ameliorate a condition, disorder, disease, orone or more symptoms thereof in a subject is about 1 mg/kg, about 5mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg,about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50mg/kg, about 60 mg/kg, about 70 mg/kg, about 80 mg/kg, about 90 mg/kg,about 100 mg/kg, about 125 mg/kg, about 150 mg/kg, about 175 mg/kg,about 200 mg/kg, about 225 mg/kg, about 250 mg/kg, about 275 mg/kg, orabout 300 mg/kg. In certain embodiments, the twice daily dosage of thecomposition provided herein, based on weight of the active compound,administered to prevent, treat, manage, or ameliorate a condition,disorder, disease, or one or more symptoms thereof in a subject isbetween (inclusive) about 1-10 mg/kg, about 10 mg/kg, about 25-50 mg/kg,about 50-100 mg/kg, about 50-150 mg/kg, about 100-150 mg/kg, about100-200 mg/kg, about 150-200 mg/kg, or about 150-250 mg/kg

In certain embodiments, administration of the same composition may berepeated and the administrations may be separated by at least 1 day, 2days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75days, 3 months, or 6 months. In other embodiments, administration of thesame prophylactic or therapeutic agent may be repeated and theadministration may be separated by at least at least 1 day, 2 days, 3days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3months, or 6 months.

In certain aspects, provided herein are unit dosages comprising acompound, or a pharmaceutically acceptable salt thereof, in a formsuitable for administration. Such forms are described in detail herein.In certain embodiments, the unit dosage comprises 1 to 1000 mg, 5 to 250mg or 10 to 50 mg active ingredient. In particular embodiments, the unitdosages comprise about 1, 5, 10, 25, 50, 100, 125, 250, 500 or 1000 mgactive ingredient. Such unit dosages can be prepared according totechniques familiar to those of skill in the art.

In certain embodiments, dosages of the second agents to be used in acombination therapy are provided herein. In certain embodiments, dosageslower than those which have been or are currently being used to treat acondition, disease, or disorder associated with abnormal activation ofthe SREBP pathway are used in the combination therapies provided herein.The recommended dosages of second agents can be obtained from theknowledge of those of skill in the art. For those second agents that areapproved for clinical use, recommended dosages are described in, forexample, Hardman et al., eds., 1996, Goodman & Gilman's ThePharmacological Basis Of Therapeutics 9^(th)Ed, Mc-Graw-Hill, New York;Physician's Desk Reference (PDR) 57^(th)Ed., 2003, Medical EconomicsCo., Inc., Montvale, N.J.; which are incorporated herein by reference intheir entirety.

In various embodiments, the therapies (e.g., a compound provided hereinand the second agent) are administered less than 5 minutes apart, lessthan 30 minutes apart, 1 hour apart, at about 1 hour apart, at about 1to about 2 hours apart, at about 2 hours to about 3 hours apart, atabout 3 hours to about 4 hours apart, at about 4 hours to about 5 hoursapart, at about 5 hours to about 6 hours apart, at about 6 hours toabout 7 hours apart, at about 7 hours to about 8 hours apart, at about 8hours to about 9 hours apart, at about 9 hours to about 10 hours apart,at about 10 hours to about 11 hours apart, at about 11 hours to about 12hours apart, at about 12 hours to 18 hours apart, 18 hours to 24 hoursapart, 24 hours to 36 hours apart, 36 hours to 48 hours apart, 48 hoursto 52 hours apart, 52 hours to 60 hours apart, 60 hours to 72 hoursapart, 72 hours to 84 hours apart, 84 hours to 96 hours apart, or 96hours to 120 hours apart. In various embodiments, the therapies areadministered no more than 24 hours apart or no more than 48 hours apart.In certain embodiments, two or more therapies are administered withinthe same patient visit. In other embodiments, the compound providedherein and the second agent are administered concurrently.

In other embodiments, the compound provided herein and the second agentare administered at about 2 to 4 days apart, at about 4 to 6 days apart,at about 1 week part, at about 1 to 2 weeks apart, or more than 2 weeksapart.

In certain embodiments, administration of the same agent may be repeatedand the administrations may be separated by at least 1 day, 2 days, 3days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3months, or 6 months. In other embodiments, administration of the sameagent may be repeated and the administration may be separated by atleast at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days,45 days, 2 months, 75 days, 3 months, or 6 months.

In certain embodiments, a compound provided herein and a second agentare administered to a patient, in certain embodiments, a mammal, such asa human, in a sequence and within a time interval such that the compoundprovided herein can act together with the other agent to provide anincreased benefit than if they were administered otherwise. In certainembodiments, the second active agent can be administered at the sametime or sequentially in any order at different points in time; however,if not administered at the same time, they should be administeredsufficiently close in time so as to provide the desired therapeutic orprophylactic effect. In certain embodiments, the compound providedherein and the second active agent exert their effect at times whichoverlap. Each second active agent can be administered separately, in anyappropriate form and by any suitable route. In other embodiments, thecompound provided herein is administered before, concurrently or afteradministration of the second active agent.

In certain embodiments, the compound provided herein and the secondagent are cyclically administered to a patient. Cycling therapy involvesthe administration of a first agent (e.g., a first prophylactic ortherapeutic agent) for a period of time, followed by the administrationof a second agent and/or third agent (e.g., a second and/or thirdprophylactic or therapeutic agent) for a period of time and repeatingthis sequential administration. Cycling therapy can reduce thedevelopment of resistance to one or more of the therapies, avoid orreduce the side effects of one of the therapies, and/or improve theefficacy of the treatment.

In certain embodiments, the compound provided herein and the secondactive agent are administered in a cycle of less than about 3 weeks,about once every two weeks, about once every 10 days or about once everyweek. One cycle can comprise the administration of a compound providedherein and the second agent by infusion over about 90 minutes everycycle, about 1 hour every cycle, about 45 minutes every cycle. Eachcycle can comprise at least 1 week of rest, at least 2 weeks of rest, atleast 3 weeks of rest. The number of cycles administered is from about 1to about 12 cycles, more typically from about 2 to about 10 cycles, andmore typically from about 2 to about 8 cycles.

In other embodiments, courses of treatment are administered concurrentlyto a patient, i.e., individual doses of the second agent areadministered separately yet within a time interval such that thecompound provided herein can work together with the second active agent.In certain embodiments, one component can be administered once per weekin combination with the other components that can be administered onceevery two weeks or once every three weeks. In other words, the dosingregimens are carried out concurrently even if the therapeutics are notadministered simultaneously or during the same day.

The second agent can act additively or synergistically with the compoundprovided herein. In certain embodiments, the compound provided herein isadministered concurrently with one or more second agents in the samepharmaceutical composition. In another embodiment, a compound providedherein is administered concurrently with one or more second agents inseparate pharmaceutical compositions. In still another embodiment, acompound provided herein is administered prior to or subsequent toadministration of a second agent. Also contemplated are administrationof a compound provided herein and a second agent by the same ordifferent routes of administration, e.g., oral and parenteral. Incertain embodiments, when the compound provided herein is administeredconcurrently with a second agent that potentially produces adverse sideeffects including, but not limited to, toxicity, the second active agentcan advantageously be administered at a dose that falls below thethreshold that the adverse side effect is elicited.

Kits

Also provided are kits for use in methods of treatment of a condition,disease, or disorder associated with abnormal activation of the SREBPpathway. The kits can include a compound or composition provided herein,a second agent or composition, and instructions providing information toa health care provider regarding usage for treating a condition,disease, or disorder associated with abnormal activation of the SREBPpathway. Instructions may be provided in printed form or in the form ofan electronic medium such as a floppy disc, CD, or DVD, or in the formof a website address where such instructions may be obtained. A unitdose of a compound or composition provided herein, or a second agent orcomposition, can include a dosage such that when administered to asubject, a therapeutically or prophylactically effective plasma level ofthe compound or composition can be maintained in the subject for atleast 1 day. In some embodiments, a compound or composition can beincluded as a sterile aqueous pharmaceutical composition or dry powder(e.g., lyophilized) composition.

In some embodiments, suitable packaging is provided. As used herein,“packaging” includes a solid matrix or material customarily used in asystem and capable of holding within fixed limits a compound providedherein and/or a second agent suitable for administration to a subject.Such materials include glass and plastic (e.g., polyethylene,polypropylene, and polycarbonate) bottles, vials, paper, plastic, andplastic-foil laminated envelopes and the like. If e-beam sterilizationtechniques are employed, the packaging should have sufficiently lowdensity to permit sterilization of the contents.

Methods of Use

Provided herein is a method for treating a condition, disease, ordisorder associated with abnormal activation of the SREBP pathway in asubject, which comprises contacting the subject with a therapeuticallyeffective amount of a di-substituted pyrazole disclosed herein, e.g., adi-substituted pyrazole of Formula (I)-(Im) (100), (200), (I)-(Im), and(Ia-1)-(Im-1) and 1-130 and Embodiment A, including a single enantiomer,a mixture of an enantiomeric pair, an individual diastereomer, a mixtureof diastereomers, an individual stereoisomer, a mixture ofstereoisomers, or a tautomeric form thereof, or a pharmaceuticallyacceptable salt, solvate, prodrug, phosphate, or active metabolitethereof.

In certain embodiments, provided herein are methods for treating acondition, disease, or disorder associated with abnormal activation ofthe SREBP pathway in a subject. In certain embodiments, the methodsencompass the step of administering to the subject in need thereof anamount of a compound effective for the treatment of a condition,disease, or disorder associated with abnormal activation of the SREBPpathway in combination with a second agent. The compound can be anycompound as described herein, and the second agent can be any secondagent described in the art or herein. In certain embodiments, thecompound is in the form of a pharmaceutical composition or dosage form,as described elsewhere herein.

Diseases which can be treated with the Compound according to any of theFormula described herein, including Compounds 1-130 and Embodiment A,include metabolic syndrome, hypertension, type 2 diabetes, dyslipidemia,obesity, pancreatic B-cell dysfunction, atherosclerosis, cellproliferative disease, reducing body weight, increasing thermogenesis,metabolic diseases, hyperlipidemia, a lipoprotein related disease,combined hyoerlipidemia (elevated cholesterol and triglycerides),Frederickson Type IIb, familial combined hyperlipidemia (inherited formof combined hyperlipidemia), familial hypertriglyceridemia, FredericksonType IV, hyperlipoproteinemia Type V, mixed hyperlipidemia, Aquiredhyperlipidemia, Fatty Liver Disease, Nonalcoholic Steatohepatitis,Neutral Lipid Storage Diseases, Chanarin-Dorfman Syndrome, TissueInflammation such as Cutaneous Psoriasis (associated with Metabolicsyndrome), coronary artery disease (atherosclerosis), post myocardialinfarction management, peripheral vascular disease, cerebrovasculardisease—thrombotic, type II diabetes mellitus, diabetic nephropathy,cancer, hepatocellular carcinoma—not amenable to surgical orlocoregional therapy, glioblastoma multiforme, prostate cancer, breastcancer, post-menopausal breast carcinoma, pancreatic adenocarcinoma,ovarian cancer, and B cell lymphoma.

Diseases which can be treated with the Compound according to any of theFormula described herein, including Compounds 1-130 and Embodiment A,include hyperlipidemia, a lipoprotein related disease, combinedhyoerlipidemia (elevated cholesterol and triglycerides), FredericksonType IIb, familial combined hyperlipidemia (inherited form of combinedhyperlipidemia), familial hypertriglyceridemia, Frederickson Type IV,hyperlipoproteinemia Type V, mixed hyperlipidemia, Aquiredhyperlipidemia, Fatty Liver Disease, Nonalcoholic Steatohepatitis,Neutral Lipid Storage Diseases, Chanarin-Dorfman Syndrome, TissueInflammation such as Cutaneous Psoriasis (associated with Metabolicsyndrome), coronary artery disease (atherosclerosis), post myocardialinfarction management, peripheral vascular disease, cerebrovasculardisease—thrombotic, type II diabetes mellitus, diabetic nephropathy,cancer, hepatocellular carcinoma—not amenable to surgical orlocoregional therapy, glioblastoma multiforme, prostate cancer, breastcancer, post-menopausal breast carcinoma, pancreatic adenocarcinoma,ovarian cancer, and B cell lymphoma.

Additional cancers which can be treated with the Compound according toany of the Formula described herein, including Compounds 1-130 andEmbodiment A, include a cancer selected from the group consisting oflung cancer, a digestive and gastrointestinal cancer, gastrointestinalstromal tumor, gastrointestinal carcinoid tumor, colon cancer, rectalcancer, anal cancer, bile duct cancer, small intestine cancer, stomach(gastric) cancer, esophageal cancer, gall bladder cancer, liver cancer,pancreatic cancer, appendix cancer, breast cancer, ovarian cancer, renalcancer, cancer of the central nervous system, skin cancer, a lymphoma,choriocarcinoma, head and neck cancer, osteogenic sarcoma, and a bloodcancer.

Assay Methods

Compounds can be assayed for efficacy in treating a condition, disease,or disorder associated with abnormal activation of the SREBP pathwayaccording to any assay known to those of skill in the art. Exemplaryassay methods are provided elsewhere herein.

Second Therapeutic Agents

In certain embodiments, the compounds and compositions provided hereinare useful in methods of treatment of a condition, disease, or disorderassociated with abnormal activation of the SREBP pathway, that comprisefurther administration of a second agent. The second agent can be anyagent known to those of skill in the art to be effective for thetreatment of a condition, disease, or disorder associated with abnormalactivation of the SREBP pathway, including those currently approved bythe United States Food and Drug Administration, or other similar body ofa country foreign to the United States.

In some embodiments, the disease is cancer and the second agent is acancer treatment. In some embodiments, the disease is cancer and thesecond agent is a chemotherapeutic agent. In some embodiments, thechemotherapeutic agent is selected from an alkylating agent (e.g.cyclophosphamide, mechlorethamine, chlorambucil, melphalan, dacarbazine(DTIC), a nitrosoureas, temozolomide (oral dacarbazine); ananthracycline (e.g. daunorubicin, doxorubicin, liposomal doxorubicin,epirubicin, idarubicin, mitoxantrone, and valrubicin); a cytoskeletaldisruptor (a taxane, e.g. paclitaxel, Albumin-bound paclitaxel anddocetaxel); epothilone; an Histone Deacetylase inhibitor (e.g.vorinostat and romidepsin); an inhibitor of Topoisomerase I (e.g.irinotecan and topotecan); an inhibitor of Topoisomerase II (e.g.etoposide, teniposide, and tafluposide); a kinase inhibitor (e.g.sorafenib, cobimetinib, cabozantanib, lapatinib, bortezomib, erlotinib,gefitinib, imatinib, vemurafenib, and vismodegib); a nucleotide analogand precursor analog (e.g. azacitidine, azathioprine, capecitabine,cytarabine, doxifluridine, fluorouracil, gemcitabine, hydroxyurea,mercaptopurine, methotrexate, and tioguanine); a peptide antibiotic(e.g. bleomycin and actinomycin); a platinum agent (e.g. carboplatin,cisplatin, and oxaliplatin); a retinoid (e.g. tretinoin, alitretinoin,and bexarotene); a vinca alkaloid or derivative (e.g. Capecitabine,vinblastine, vincristine, vindesine, and vinorelbine); eribulin;ixabepilone; radiation; bevacizumab; olaparib; an aromatase inhibitor(e.g. letrozole, anastrozole, and exemestane); rituximab; ibritumomab;prednisone; and enzalutamide.

In some embodiments, the disease is cancer and the second agent is akinase inhibitor e.g. sorafenib, cobimetinib, cabozantanib, lapatinib,bortezomib, erlotinib, gefitinib, imatinib, vemurafenib, and vismodegib.In some embodiments, the disease is cancer and the second agent is akinase inhibitor such as sorafenib or erlotinib.

In some embodiments, the disease is breast cancer (e.g. pos-menopausalbreast carcinoma) and the second agent is radiation, docetaxel,paclitaxel, platinum agents (cisplatin, carboplatin), vinorelbine,capecitabine, liposomal doxorubicin, gemcitabine, mitoxantrone,ixabepilone, albumin-bound paclitaxel, eribulin, trastuzumab,pertuzimab, ado-trastuzumab, lapatinib, bevacizumab, olaparib,radiation, an aromatase inhibitor (e.g. letrozole, anastrozole, andexemestane), or tamoxifen.

In some embodiments, the disease is liver cancer (e.g. hepatocellularcarcinoma, hepatocellular carcinoma not amenable to surgical orlocoregional therapy) and the second agent is sorafenib.

In some embodiments, the disease is prostate cancer and the second agentis radiation, abiraterone, or enzalutamide.

In some embodiments, the disease is pancreatic adenocarcinoma and thesecond agent is radiation.

In some embodiments, the disease is ovarian cancer and the second agentis bevacizumab, olaparib, radiation, an aromatase inhibitor (e.g.letrozole, anastrozole, and exemestane), or tamoxifen.

In some embodiments, the disease is B cell lymphoma and the second agentis rituximab, radiation, ibritumomab, cyclophosphamide, doxorubicin,vincristine, or prednisone.

In certain embodiments, a compound provided herein is administered incombination with one second agent. In further embodiments, a compoundprovided herein is administered in combination with two second agents.In still further embodiments, a compound provided herein is administeredin combination with two or more second agents.

As used herein, the term “in combination” includes the use of more thanone therapy (e.g., one or more prophylactic and/or therapeutic agents).The use of the term “in combination” does not restrict the order inwhich therapies (e.g., prophylactic and/or therapeutic agents) areadministered to a subject with a disorder. A first therapy (e.g., aprophylactic or therapeutic agent such as a compound provided herein)can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes,45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequentto (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or12 weeks after) the administration of a second therapy (e.g., aprophylactic or therapeutic agent) to a subject with a disorder.

As used herein, the term “synergistic” includes a combination of acompound provided herein and another therapy (e.g., a prophylactic ortherapeutic agent) which has been or is currently being used to prevent,manage or treat a disorder, which is more effective than the additiveeffects of the therapies. A synergistic effect of a combination oftherapies (e.g., a combination of prophylactic or therapeutic agents)permits the use of lower dosages of one or more of the therapies and/orless frequent administration of said therapies to a subject with adisorder. The ability to utilize lower dosages of a therapy (e.g., aprophylactic or therapeutic agent) and/or to administer said therapyless frequently reduces the toxicity associated with the administrationof said therapy to a subject without reducing the efficacy of saidtherapy in the prevention or treatment of a disorder). In addition, asynergistic effect can result in improved efficacy of agents in theprevention or treatment of a disorder. Finally, a synergistic effect ofa combination of therapies (e.g., a combination of prophylactic ortherapeutic agents) may avoid or reduce adverse or unwanted side effectsassociated with the use of either therapy alone.

The active compounds provided herein can be administered in combinationor alternation with another therapeutic agent, in particular an agenteffective in the treatment of a condition, disease, or disorderassociated with abnormal activation of the SREBP pathway. In combinationtherapy, effective dosages of two or more agents are administeredtogether, whereas in alternation or sequential-step therapy, aneffective dosage of each agent is administered serially or sequentially.The dosages given will depend on absorption, inactivation and excretionrates of the drug as well as other factors known to those of skill inthe art. It is to be noted that dosage values will also vary with theseverity of the condition, disease, or disorder associated with abnormalactivation of the SREBP pathway to be treated. It is to be furtherunderstood that for any particular subject, specific dosage regimens andschedules should be adjusted over time according to the individual needand the professional judgment of the person administering or supervisingthe administration of the compositions.

General Scheme 1 describes the preparation of a Compound of Formula (I)where R¹ is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl;where the phenyl, pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinylrings are optionally substituted with 1 or 2 R^(1a); each X isindependently a leaving group such as halo (in some embodiments, bromo);each R is hydrogen, each R is linear alkyl, or the two R are alkyl andtogether with the atoms to which they are attached form a cyclic boronicacid or ester; and all other groups are as defined in the Summary of theinvention or in any embodiments described herein.

General Scheme 2 describes the preparation of a Compound of Formula (I)where R¹ is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl;where the phenyl, pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinylrings are optionally substituted with 1 or 2 R^(1a); R^(6b) is alkyl,haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, orheterocycloalkylalkyl), and additionally optionally substituted with 1or 2 R^(2b); R″ is H or alkyl; and all other groups are as defined inthe Summary of the invention or in any embodiments described herein.

General Scheme 3 describes the preparation of a Compound of Formula (I)where R¹ is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl;where the phenyl, pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinylrings are optionally substituted with 1 or 2 R^(1a); X is a leavinggroup such as halo (in some embodiments, bromo); each R is hydrogen,each R is linear alkyl, or the two R are alkyl and together with theatoms to which they are attached form a cyclic boronic acid or ester;and all other groups are as defined in the Summary of the invention orin any embodiments described herein; where the —NH₂ is furtherderivatized according to Step D in General Scheme 1 or according toGeneral Scheme 2.

General Scheme 4 describes the preparation of a Compound of Formula (I)where R¹ is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl;where the phenyl, pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinylrings are optionally substituted with 1 or 2 R^(1a); each X isindependently a leaving group such as halo (in some embodiments, bromo);and all other groups are as defined in the Summary of the invention orin any embodiments described herein; where the —NH₂ is furtherderivatized according to Step D in General Scheme 1 or according toGeneral Scheme 2.

General Scheme 5 describes the preparation of a Compound of Formula (I)where R¹ is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl;where the phenyl, pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinylrings are optionally substituted with 1 or 2 R^(1a); X is a leavinggroup such as halo (in some embodiments, bromo); each R is hydrogen,each R is linear alkyl, or the two R are alkyl and together with theatoms to which they are attached form a cyclic boronic acid or ester;and all other groups are as defined in the Summary of the invention orin any embodiments described herein; where the —NH₂ is furtherderivatized according to Step D in General Scheme 1 or according toGeneral Scheme 2.

General Scheme 6 describes the preparation of a Compound of Formula (I)where R¹ is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl;where the phenyl, pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinylrings are optionally substituted with 1 or 2 R^(1a); X is a leavinggroup such as halo (in some embodiments, bromo); each R is hydrogen,each R is linear alkyl, or the two R are alkyl and together with theatoms to which they are attached form a cyclic boronic acid or ester;and all other groups are as defined in the Summary of the invention orin any embodiments described herein; where the —NH₂ is furtherderivatized according to Step D in General Scheme 1 or according toGeneral Scheme 2.

General Scheme 7 describes the preparation of a Compound of Formula (I)where R^(6b) is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, or heterocycloalkylalkyl; R″ is H or alkyl; R²′ is

and all other groups are as defined in the Summary of the invention orin any embodiments described herein.

General Scheme 8 describes the preparation of a Compound of Formula (I)where R^(5b) is alkyl, haloalkyl, cycloalkylalkyl, orheterocycloalkylalkyl; R²′ is

and all other groups are as defined in the Summary of the invention orin any embodiments described herein.

General Scheme 9 describes the preparation of a Compound of Formula (I)where R¹ is pyridinonyl substituted with one R^(1b) and optionallysubstituted with one R^(1a); other groups are as defined in the Summaryof the invention or in any embodiments described herein.

EXAMPLES

As used herein, the symbols and conventions used in these processes,schemes and examples, regardless of whether a particular abbreviation isspecifically defined, are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Specifically, butwithout limitation, the following abbreviations may be used in theexamples and throughout the specification: g (grams); mg (milligrams);mL (milliliters); L (microliters); mM (millimolar); μM (micromolar); Hz(Hertz); MHz (megahertz); mmol (millimoles); hr or hrs (hours); min(minutes); MS (mass spectrometry); ESI (electrospray ionization); TLC(thin layer chromatography); HPLC (high pressure liquid chromatography);THF (tetrahydrofuran); CDCl₃ (deuterated chloroform); AcOH (aceticacid); DCM (dichloromethane); DMSO (dimethylsulfoxide); DMSO-d₆(deuterated dimethylsulfoxide); EtOAc (ethyl acetate); MeOH (methanol);Tces (2,2,2-trichloroethoxysulfonyl); —Si(tert-Bu)(Ph)₂ and —Si^(t)BuPh₂(tert-butyl-diphenylsilyl); and BOC (t-butyloxycarbonyl).

For all of the following examples, standard work-up and purificationmethods known to those skilled in the art can be utilized. Unlessotherwise indicated, all temperatures are expressed in ° C. (degreesCelsius). All reactions are conducted at room temperature unlessotherwise noted. Synthetic methodologies illustrated herein are intendedto exemplify the applicable chemistry through the use of specificexamples and are not indicative of the scope of the disclosure.

Example 1:N-(4-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)phenyl)cyclopropanesulfonamide

Step 1: 4-(4-bromo-1H-pyrazol-1-yl)-2-propylpyridine

To a stirred solution of 4-bromo-2-(n-propyl)pyridine (4.00 g, 20.0mmol), 3-bromopyrazole (3.526 g, 24.0 mmol), potassium carbonate (5.526g, 40.0 mmol) in anhydrous toluene (40 mL) under argon were addedtrans-N,N′-dimethyl-1,2-cyclohexanediamine (0.63 mL, 4.0 mmol) andcopper(I) iodide (0.190 g, 1.0 mmol). The mixture was stirred at 100° C.overnight. After cooling, the mixture was partitioned between ethylacetate and water. The layers were separated and the aqueous layer wasextracted twice with ethyl acetate. The combined organics were washedwith brine and dried over MgSO₄. The solvents were removed and resultingresidue was dissolved in DCM and loaded to silica gel column (80 g,0-40% ethyl acetate/hexanes). The title compound was obtained as a thickoil (2.89 g, 54.3%). LC/MS: 268.1 [M+1]⁺; ¹H NMR (300 MHz, CDCl₃): δ8.59 (d, J=5.1 Hz, 1H), 8.06 (s, 1H), 7.73 (s, 1H), 7.49 (d, J=1.8 Hz,1H), 7.38 (dd, J=5.7, 2.4 Hz, 1H), 2.84 (t, J=7.5 Hz, 2H), 1.85-1.78 (m,2H), 1.00 (t, J=7.5 Hz, 3H).

Step 2: 4-(4-(4-nitrophenyl)-1H-pyrazol-1-yl)-2-propylpyridine

A solution of 4-(4-bromo-1H-pyrazol-1-yl)-2-propylpyridine (2.370 g, 8.9mmol), 4-Nitrophenylboronic acid (1.858 g, 11.1 mmol), potassiumcarbonate (13.36 mL of a 2.0 molar aqueous solution, 26.7 mmol) in DMF(20 mL) was stirred at room temperature for 5 minutes, then palladiumdiacetate (300 mg) was then added and the flask was flushed with argonand stirred at 90° C. for 4 hours. After cooling, the mixture waspartitioned between ethyl acetate (100 mL) and water. The organic layerwas washed with brine, dried over Na₂SO₄ and concentrated. The residuewas purified by silica gel column (0-45% ethyl acetate/hexanes) toafford the desired product as a yellow solid (1.2 g, 43.7%). ¹H-NMR (300MHz, CDCl₃): δ 8.62 (d, J=4.8 Hz, 1H), 8.39-8.36 (m, 2H), 8.28-8.25 (m,2H), 8.13 (s, 1H), 7.81-7.71 (m, 3H), 2.88 (t, J=7.8 Hz, 2H), 1.88-1.81(m, 2H), 1.03 (t, J=7.8 Hz, 3H).

Step 3: 4-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)aniline

To a suspension of4-(4-(4-nitrophenyl)-1H-pyrazol-1-yl)-2-propylpyridine (1.2 g, 3.9 mmol)in Ethanol (70 mL), was added Tin(II) chloride (2.435 g, 12.8 mmol)followed by hydrogen chloride (5 mL), and the reaction was heated to 80°C. for 5 hours to give a yellow suspension. After the reaction hadcooled to ambient temperature, it was poured into an ice-cold solutionof 10.0 g potassium hydroxide in 100 mL of water and diluted with 75 mLof ethyl acetate, the layers separated, and the aqueous layer wasextracted with ethyl acetate (3×30 mL). The combined organics were driedover sodium sulfate and concentrated. The residue was purified by silicagel column (0-100% ethyl acetate/hexanes) to afford the desired productas a yellow solid (0.64 g, 59.1%). ¹H-NMR (300 MHz, CDCl₃): δ 8.57 (d,J=6.0 Hz, 1H), 8.14 (s, 1H), 7.97 (s, 1H), 7.55 (s, 1H), 7.44 (dd,J=5.4, 1.8 Hz, 1H), 7.37 (d, J=8.7 Hz, 2H), 6.75 (d, J=8.1 Hz, 2H), 3.75(bs, 2H), 2.85 (t, J=7.7 Hz, 2H), 1.87-1.79 (m, 2H), 1.02 (t, J=7.4 Hz,3H).

Step 4:N-(4-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)phenyl)cyclopropanesulfonamide

A solution of 4-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)aniline (0.09g, 0.3 mmol) and Pyridine (78 μL, 1.0 mmol) in Dichloromethane (5 mL)was cooled to 0° C. Then, Cyclopropanesulfonyl chloride (99 μL, 1.0mmol) was added, and reaction mixture was allowed to warm to roomtemperature overnight to give a clear reddish brown solution. Reactionmixture was cooled back to 0° C., and it was quenched with saturatedsodium bicarbonate. The layers were separated, and the aqueous layer wasextracted with dichloromethane (2×20 mL). The combined organics weredried over Na₂SO₄ and concentrated. The resulting residue was purifiedby silica gel chromatography (0-50% ethyl acetate/hexanes). The titlecompound was obtained as a yellow solid (0.056 g, 43.8%). LC/MS: [M+1]⁺,383.0; ¹H NMR (300 MHz, CDCl₃): δ 8.60 (d, J=5.4 Hz, 1H), 8.25 (s, 1H),8.03 (s, 1H), 7.58-7.47 (m, 4H), 7.34 (s, 1H), 7.31 (s, 1H), 6.38 (brs,1H), 2.87 (t, J=7.7 Hz, 2H), 2.54-2.50 (m, 1H), 1.88-1.80 (m, 2H),1.26-1.19 (m, 3H), 1.05-0.99 (m, 4H).

Example 2:1-cyclopropyl-N-(4-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)phenyl)methanesulfonamide

A solution of 4-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)aniline (0.090g, 0.3 mmol) and Pyridine (78 μL, 1.0 mmol) in Dichloromethane (5 mL)was cooled to 0° C. Then cyclopropylmethanesulfonyl chloride (150 mg,1.0 mmol) was added, and reaction mixture was allowed to warm to roomtemperature overnight to give a clear reddish brown solution. Thereaction mixture was cooled back to 0° C., and it was quenched withsaturated sodium bicarbonate. The layers were separated, and the aqueouslayer was extracted with dichloromethane (2×20 mL). The combinedorganics were dried over Na₂SO₄ and concentrated. The resulting residuewas purified by silica gel chromatography (0-50% ethyl acetate/hexanes).The title compound was obtained as a yellow solid (0.089 g, 67.9%).LC/MS: [M+1]⁺, 397.1; ¹HNMR (300 MHz, CDCl₃): δ 8.60 (d, J=5.7 Hz, 1H),8.23 (s, 1H), 8.01 (s, 1H), 7.57-7.46 (m, 4H), 7.31-7.27 (m, 2H), 6.78(brs, 1H), 3.08 (d, J=7.5 Hz, 2H), 2.86 (t, J=7.5 Hz, 2H), 1.90-1.77 (m,2H), 1.26-1.12 (m, 1H), 1.02 (t, J=7.4 Hz, 3H), 0.74-0.68 (m, 2H),0.35-0.30 (m, 2H)

Example 3:N-isobutyl-4-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)aniline

To a solution of 4-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)aniline(0.10 g, 0.4 mmol) in dichloroethane (5 mL) was added isobutyraldehyde(0.039 mL, 0.4 mmol), acetic acid (0.031 mL, 0.5 mmol) and Sodiumtriacetoxyborohydride (0.152 g, 0.7 mmol). The reaction was stirred atroom temperature for 4 hours. The mixture was diluted with sat. sodiumbicarbonate solution and dichloromethane. The organic layer was washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated. The resulting residue was purified by silica gelchromatography (0-50% ethyl acetate/hexanes). The title compound wasobtained as a yellow oil (0.097 g, 79.5%). LC-MS: 335.2 [M+1]⁺; ¹H NMR(300 MHz, CDCl₃): δ 8.57 (d, J=5.4 Hz, 1H), 8.12 (s, 1H), 7.96 (s, 1H),7.56-7.55 (m, 1H), 7.44 (dd, J=5.4, 1.8 Hz, 1H), 7.38 (d, J=8.1 Hz, 2H),6.66 (d, J=8.7 Hz, 2H), 3.84 (brs, 1H), 2.98 (d, J=6.6 Hz, 2H), 2.85 (t,J=7.7 Hz, 2H), 1.97-1.77 (m, 3H), 1.04-0.99 (m, 9H).

Example 4:N-(4-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)phenyl)propane-2-sulfonamide

A solution of 4-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)aniline (0.080g, 0.3 mmol) and Pyridine (70 μL, 0.9 mmol) in Dichloromethane (5 mL)was cooled to 0° C. Then, propane-2-sulfonyl chloride (97 μL, 0.9 mmol)was added, and reaction mixture was allowed to warm to room temperatureovernight to give a clear reddish brown solution. The reaction mixturewas cooled back to 0° C., and it was quenched with saturated sodiumbicarbonate. The layers were separated, and the aqueous layer wasextracted with dichloromethane (2×20 mL). The combined organics weredried over Na₂SO₄ and concentrated. The resulting residue was purifiedby silica gel chromatography (0-50% ethyl acetate/hexanes). The titlecompound was obtained as a yellow solid (0.038 g, 33.4%). LC/MS: 385.1[M+1]⁺; ¹H NMR (300 MHz, CDCl₃): δ 8.60 (d, J=5.7 Hz, 1H), 8.23 (s, 1H),8.01 (s, 1H), 7.58-7.46 (m, 4H), 7.31 (s, 2H), 6.40 (brs, 1H), 3.37-3.30(m, 1H), 2.86 (t, J=7.5 Hz, 2H), 1.87-1.80 (m, 2H), 1.44 (d, J=6.6 Hz,6H), 1.02 (t, J=7.4 Hz, 3H).

Example 5:N-(5-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-yl)cyclopropanesulfonamide

Step 1: 5-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine

A solution of 4-(4-bromo-1H-pyrazol-1-yl)-2-propylpyridine (0.510 g, 1.9mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine(0.485 g, 2.2 mmol) and 2.0 M sodium carbonate (2.9 mL, 5.7 mmol) in DMF(10 mL) was stirred at room temperature for 5 minutes, thentetrakis(triphenylphosphine) pallladium(0) (50 mg) was then added andthe flask was flushed with argon and stirred at 110° C. for overnight.After cooling, the mixture was partitioned between ethyl acetate (100mL) and water. The organic layer was washed with brine, dried oversodium sulfate and concentrated. The residue was purified by silica gelchromatography (25 g, 0-30% ethyl acetate/hexanes) to afford the desiredproduct as a light yellow solid (0.35 g, 65.4%). ¹H NMR (300 MHz,CDCl₃): δ 8.58 (d, J=5.7 Hz, 1H), 8.31 (m, 1H), 8.17 (s, 1H), 7.96 (s,1H), 7.63 (d, J=6.9 Hz, 1H), 7.56 (s, 1H), 7.46 (d, J=8.1 Hz, 1H), 6.59(d, J=8.1 Hz, 1H), 4.57 (brs, 2H), 2.85 (t, J=7.7 Hz, 2H), 1.87-1.79 (m,2H), 1.04 (t, J=7.4 Hz, 3H).

Step 2:N-(5-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-yl)cyclopropanesulfonamide

A solution of5-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine (0.080 g,0.3 mmol) and Pyridine (69 μL, 0.9 mmol) in Dichloromethane (6 mL) wascooled to 0° C. Then, Cyclopropanesulfonyl chloride (88 μL, 0.9 mmol)was added, and the reaction mixture was allowed to warm to RT overnightto give a clear reddish brown solution. The reaction mixture was cooledback to 0° C., and it was quenched with saturated sodium bicarbonate.The layers were separated, and the aqueous layer was extracted withdichloromethane (2×20 mL). The combined organics were dried over Na₂SO₄and concentrated. The resulting residue was purified by silica gelchromatography (0-50% ethyl acetate/hexanes). The title compound wasobtained as a yellow solid (0.019 g, 16.9%). LC/MS: [M+1]⁺, 384.1; ¹HNMR(300 MHz, CDCl₃): δ 8.62 (d, J=5.4 Hz, 1H), 8.53 (s, 1H), 8.27 (s, 1H),8.03 (s, 1H), 7.88-7.86 (m, 1H), 7.58 (s, 1H), 7.49-7.46 (m, 2H), 2.87(t, J=7.7 Hz, 2H), 2.74-2.62 (m, 1H), 1.88-1.80 (m, 2H), 1.29-1.26 (m,3H), 1.05-1.00 (m, 4H).

Example 6:N-isopropyl-4-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)aniline

To a solution of 4-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)aniline(0.080 g, 0.3 mmol) in dichloroethane (5 mL) was added acetone (106 μL,1.4 mmol), acetic acid (25 μL, 0.4 mmol) and sodiumtriacetoxyborohydride (0.182 g, 0.9 mmol). The reaction was stirred atroom temperature overnight. The reaction mixture partitioned betweendichloromethane and saturated sodium bicarbonate solution. The layerswere separated and the aqueous layer was extracted twice withdichloromethane. The combined organics were dried over MgSO₄. Thesolvents were removed and the resulting residue was purified by silicagel chromatography (0-60% ethyl acetate/hexanes). The title compound wasobtained as a yellow solid (0.074 g, 79.1%). LC/MS: 321.2 [M+1]⁺; ¹H NMR(300 MHz, CDCl₃): δ 8.57 (d, J=6.0 Hz, 1H), 8.12 (s, 1H), 7.96 (s, 1H),7.44 (dd, J=5.7, 2.1 Hz, 1H), 7.46-7.43 (m, 1H), 7.38 (d, J=8.1 Hz, 2H),6.64 (d, J=8.4 Hz, 2H), 3.72-3.58 (m, 1H), 2.85 (t, J=8.0 Hz, 2H),1.87-1.77 (m, 2H), 1.25 (d, J=6.0 Hz, 6H), 1.01 (t, J=7.4 Hz, 3H).

Example 7:N-isopropyl-5-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine

To a solution of5-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine (0.47 g, 1.7mmol) in dichloroethane (40 mL) was added acetone (618 μL, 8.4 mmol),acetic acid (144 μL, 2.5 mmol) and Sodium triacetoxyborohydride (1.065g, 5.0 mmol). The reaction was stirred at room temperature overnight.The reaction mixture partitioned between dichloromethane and saturatedsodium bicarbonate solution. The layers were separated and the aqueouslayer was extracted twice with dichloromethane. The combined organicswere dried over MgSO₄. The solvents were removed and the resultingresidue was purified by silica gel chromatography (0-60% ethylacetate/hexanes). The title compound was obtained as an off-white solid(87 mg, 16.0%). LC/MS: 322.1 [M+1]⁺; ¹H NMR (300 MHz, CDCl₃): δ 8.58 (d,J=6.0 Hz, 1H), 8.32 (d, J=2.4 Hz, 1H), 8.14 (s, 1H), 7.95 (s, 1H), 7.60(dd, J=6.0, 2.4 Hz, 1H), 7.56 (s, 1H), 7.45 (dd, J=5.7, 1.8 Hz, 1H),6.44 (d, J=8.1 Hz, 1H), 4.47 (brs, 1H), 3.96-3.89 (m, 1H), 2.85 (t,J=7.7 Hz, 2H), 1.87-1.79 (m, 2H), 1.27 (d, J=6.3 Hz, 6H), 1.01 (t, J=7.4Hz, 3H).

Example 8:N-isobutyl-5-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine

To a solution of5-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine (0.200 g,0.7 mmol) in dichloroethane (10 mL) was added isobutyraldehyde (79 μL,0.9 mmol), acetic acid (61 μL, 1.1 mmol) and Sodiumtriacetoxyborohydride (0.302 g, 1.4 mmol). The reaction was stirred atroom temperature for 4 hours. The mixture was diluted with saturatedsodium bicarbonate and dichloromethane. The organic layer was washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated. The resulting residue was purified by silica gelchromatography (0-50% ethyl acetate/hexanes). The title compound wasobtained as an off-white solid (77 mg, 32.5%). LC/MS: 336.2 [M+1]⁺; ¹HNMR (300 MHz, CDCl₃): δ 8.58 (d, J=5.4 Hz, 1H), 8.31 (d, J=1.8 Hz, 1H),8.14 (s, 1H), 7.95 (s, 1H), 7.60 (dd, J=8.7, 2.1 Hz, 1H), 7.56 (s, 1H),7.52-7.44 (m, 1H), 6.46 (d, J=8.7 Hz, 1H), 4.72 (brs, 1H), 3.13 (t,J=6.2 Hz, 2H), 2.85 (t, J=7.7 Hz, 2H), 1.97-1.77 (m, 3H), 1.04-0.99 (m,9H).

Example 9:N-(3-chloro-4-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)phenyl)methanesulfonamide

Step 1:2-propyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyridine

To a stirred solution of 4-(4-bromo-1H-pyrazol-1-yl)-2-propylpyridine(2.100 g, 7.9 mmol) in DMSO (35 mL) was added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (3.006 g,11.8 mmol) and potassium acetate (2.323 g, 23.7 mmol) followed by1,1′-bis(diphenylphosphino)ferrocenedichloro palladium(II)dichloromethane complex (190 mg) and the flask was flushed with argonand stirred at 70° C. for overnight. After cooling, the mixture waspartitioned between ethyl acetate (100 mL) and saturated sodiumbicarbonate. The organic layer was washed with brine, dried over Na₂SO₄and concentrated. The product was obtained as a yellow oil (3.0 g). Thecrude was directly used in subsequent reactions without furtherpurification. LC/MS: [M+1]⁺, 314.2.

Step 2: 4-(4-(2-chloro-4-nitrophenyl)-1H-pyrazol-1-yl)-2-propylpyridine

A mixture of crude2-propyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyridine(3.0 g, 6.7 mmol), 1-bromo-2-chloro-4-nitrobenzene (2.378 g, 10.1 mmol)and 2.0 M sodium carbonate (10.06 mL, 20.1 mmol) in DMF (30 mL) wasstirred at room temperature for 5 minutes, thentetrakis(triphenylphosphine) pallladium(0) (160 mg) was then added andthe flask was flushed with argon and stirred at 110° C. for overnight.After cooling, the mixture was partitioned between ethyl acetate (200mL) and water. The organic layer was washed with brine, dried overNa₂SO₄ and concentrated. The residue was purified by silica gelchromatography (0-30% ethyl acetate/hexanes) to afford the desiredproduct as a light yellow solid (1.14 g, 49%). LC/MS: [M+1]⁺, 343.2;¹H-NMR (300 MHz, CDCl₃): δ 8.62 (d, J=4.8 Hz, 1H), 8.58 (s, 1H), 8.41(s, 1H), 8.21-8.16 (m, 2H), 7.72 (d, J=9.0 Hz, 1H), 7.60 (s, 1H),7.52-7.50 (m, 1H), 2.88 (t, J=7.8 Hz, 2H), 1.90-1.78 (m, 2H), 1.04 (t,J=7.8 Hz, 3H).

Step 3: 3-chloro-4-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)aniline

To a suspension of4-(4-(2-chloro-4-nitrophenyl)-1H-pyrazol-1-yl)-2-propylpyridine (1.100g, 3.2 mmol) in ethanol (70 mL), was added Tin(II) chloride (2.008 g,10.6 mmol) followed by concentrated hydrogen chloride (5 mL), and thereaction was heated to 80° C. for 8 hours to give a yellow suspension.After the reaction had cooled to ambient temperature, it was poured intoan ice-cold solution of 10.0 g potassium hydroxide in 100 mL of waterand diluted with 75 mL of ethyl acetate, the layers separated, and theaqueous layer was extracted with ethyl acetate (3×30 mL). The combinedorganics were dried over sodium sulfate and concentrated. The residuewas purified by silica gel chromatography (0 to 100% ethylacetate/hexanes) to afford the desired product as a yellow solid (0.84g, 84%). LC/MS: [M+1]⁺, 313.1; ¹H-NMR (300 MHz, CDCl₃): δ 8.58 (d, J=6.0Hz, 1H), 8.31 (s, 1H), 7.99 (s, 1H), 7.56 (s, 1H), 7.46 (dd, J=5.7, 1.8Hz, 1H), 7.29 (d, J=8.1 Hz, 1H), 6.82 (d, J=1.8 Hz, 1H), 6.64 (dd,J=8.4, 2.4 Hz, 1H), 3.82 (s, 2H), 2.85 (t, J=7.7 Hz, 2H), 1.87-1.79 (m,2H), 1.01 (t, J=7.4 Hz, 3H).

Step 4:N-(3-chloro-4-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)phenyl)methanesulfonamide

A round bottom flask was charged with3-chloro-4-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)aniline (0.08 g,0.26 mmol), dichloromethane (5 mL) and Pyridine (0.0310 mL, 0.38 mmol)and the reaction mixture cooled to 0° C. Methanesulfonyl chloride (0.03mL, 0.38 mmol) was slowly added under nitrogen and the reaction mixturewas stirred at 0° C. for 30 minutes. The mixture was allowed to warm toroom temperature and stirred for additional 3 hours. The mixture wasdiluted with saturated sodium bicarbonate and dichloromethane. Theorganic layer was washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated. The residue was purified by silicagel chromatography (0-60% ethyl acetate/hexanes). The title compound wasobtained as an off-white solid (0.049 g, 47%). LC/MS: [M+1]⁺, 391.0;¹HNMR (300 MHz, CDCl3), δ 8.61 (d, J=5.4 Hz, 1H), 8.40 (s, 1H), 8.05 (s,1H), 7.58 (d, J=1.5 Hz, 1H), 7.53-7.47 (m, 2H), 7.40 (d, J=2.4 Hz, 1H),7.21 (dd, J=8.7, 2.4 Hz, 1H), 6.76 (brs, 1H), 3.10 (s, 3H), 2.87 (t,J=7.7 Hz, 2H), 1.87-1.80 (m, 2H), 1.02 (t, J=7.7 Hz, 3H).

Example 10:N-(3-chloro-4-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)phenyl)cyclopropanesulfonamide

A solution of3-chloro-4-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)aniline (0.076 g,0.2 mmol) and Pyridine (58 μL, 0.7 mmol) in Dichloromethane (5 mL) wascooled to 0° C. Then, Cyclopropanesulfonyl chloride (73 μL, 0.7 mmol)was added, and the reaction mixture was allowed to warm to roomtemperature overnight to give a clear reddish brown solution. Thereaction mixture was cooled back to 0° C., and it was quenched withsaturated sodium bicarbonate. The layers were separated, and the aqueouslayer was extracted with dichloromethane (2×20 mL). The combinedorganics were dried over Na₂SO₄ and concentrated. The residue waspurified by silica gel chromatography (0-50% ethyl acetate/hexanes). Thetitle compound was obtained as an off-white solid (0.072 g, 72%). LC/MS:[M+1]⁺, 417.0; ¹HNMR (300 MHz, CDCl₃): δ 8.61 (d, J=6.0 Hz, 1H), 8.41(s, 1H), 8.05 (s, 1H), 7.58 (d, J=1.5 Hz, 1H), 7.51-7.48 (m, 2H), 7.42(d, J=1.8 Hz, 1H), 7.26-7.22 (m, 1H), 6.60 (brs, 1H), 2.86 (t, J=7.7 Hz,2H), 2.58-2.54 (m, 1H), 1.87-1.80 (m, 2H), 1.32-1.23 (m, 2H), 1.08-0.99(m, 5H).

Example 11:N-(3-chloro-4-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)phenyl)-1,1,1-trifluoromethanesulfonamide

Pyridine (0.078 mL, 1.0 mmol) was added dropwise to a solution oftriflic anhydride (0.11 mL, 0.6 mmol) at 0° C. under nitrogen indichloromethane (5 mL) over 10 minutes. The reaction mixture was stirredat the same temperature for 30 minutes. A solution of3-chloro-4-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)aniline (0.100 g,0.3 mmol) in dichlormethane (3 mL) was added dropwise over 20 minutes.The reaction was then allowed to come to room temperature and stirredfor 1 hour. Upon completion, ice water was added and the dichloromethanelayer was separated. The aqueous was extracted with dichloromethane(2×50 mL). The dichloromethane extracts were combined and dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (0-70% ethylacetate/hexanes). The title compound was obtained as a yellow solid(0.036 g, 24.9%). LC/MS: [M+1]⁺, 445.0; ¹HNMR (300 MHz, CDCl3), δ 8.61(d, J=5.4 Hz, 1H), 8.43 (s, 1H), 8.06 (s, 1H), 7.60-7.47 (m, 4H),7.31-7.30 (m, 1H), 2.86 (t, J=7.5 Hz, 2H), 1.86-1.79 (m, 2H), 1.01 (t,J=7.2 Hz, 3H).

Example 12:1,1,1-trifluoro-N-(5-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-yl)methanesulfonamide

Pyridine (0.078 mL, 1.0 mmol) was added dropwise to a solution oftriflic anhydride (0.108 mL, 0.6 mmol) at 0° C. under nitrogen indichloromethane (5 mL) over 10 minutes. The reaction mixture was stirredat the same temperature for 30 minutes. A solution of5-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine (0.090 g,0.3 mmol) in dichloromethane (3 mL) was added dropwise over 20 min. Thereaction was then allowed to come to room temperature and stirred for 1hour. Upon completion, ice water was added and the dichloromethane layerwas separated. The aqueous layer was extracted with dichloromethane(2×50 mL). The dichloromethane extracts were combined and dried overanhydrous sodium sulfate and concentrated under reduced. The residue waspurified by silica gel chromatography (4 g, 0-70% ethylacetate/hexanes). The title compound was obtained as a yellow solid(0.015 g, 11.3%). LC/MS: [M+1]⁺, 412.0; ¹HNMR (300 MHz, CDCl3): δ 8.65(d, J=5.4 Hz, 1H), 8.39 (s, 1H), 8.32 (s, 1H), 8.18-7.96 (m, 3H), 7.60(s, 1H), 7.53 (d, J=5.4 Hz, 1H), 2.89 (t, J=7.7 Hz, 2H), 1.89-1.81 (m,2H), 1.03 (t, J=7.4 Hz, 3H).

Example 13:3-chloro-N-isopropyl-4-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)aniline

To a solution of3-chloro-4-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)aniline (0.150 g,0.5 mmol) in dichloroethane (5 mL) was added Acetone (176 μL, 2.4 mmol),acetic acid (41 μL, 0.7 mmol) and Sodium triacetoxyborohydride (0.303 g,1.4 mmol). The reaction was stirred at room temperature overnight. Thereaction mixture partitioned between dichloromethane and saturatedsodium bicarbonate solution. The layers were separated and the aqueouslayer was extracted twice with dichloromethane. The combined organicswere dried over MgSO₄. The solvents were removed and the residue waspurified by silica gel chromatography (0-30% ethyl acetate/hexanes). Thetitle compound was obtained as a yellow oil (91 mg, 53%). LC/MS: 355.2[M+1]⁺; ¹H NMR (300 MHz, CDCl₃): δ 8.57 (d, J=5.4 Hz, 1H), 8.30 (s, 1H),7.99 (s, 1H), 7.56 (d, J=1.8 Hz, 1H), 7.46 (dd, J=5.4, 2.1 Hz, 1H), 7.30(s, 1H), 6.69 (d, J=2.4 Hz, 1H), 6.53 (dd, J=8.7 and 2.4 Hz, 1H),3.67-3.62 (m, 1H), 2.85 (t, J=7.7 Hz, 2H), 1.87-1.79 (m, 2H), 1.25 (d,J=5.7 Hz, 6H), 1.01 (t, J=7.2 Hz, 3H).

Example 14:3-chloro-N-isobutyl-4-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)aniline

To a solution of3-chloro-4-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)aniline (0.075 g,0.2 mmol) in dichloroethane (5 mL) was added isobutyraldehyde (26 μL,0.3 mmol), acetic acid (21 μL, 0.4 mmol) and sodiumtriacetoxyborohydride (0.101 g, 0.5 mmol). The reaction was stirred atroom temperature for 4 hours. The mixture was diluted with saturatedsodium bicarbonate and dichloromethane. The organic layer was washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated. The residue was purified by silica gel chromatography(0-50% ethyl acetate/hexanes). The title compound was obtained as ayellow oil (0.076 g, 83.2%). LC/MS: 369.2 [M+1]⁺; ¹H NMR (300 MHz,CDCl₃): δ 8.57 (d, J=6.0 Hz, 1H), 8.30 (s, 1H), 7.99 (s, 1H), 7.57 (d,J=1.8 Hz, 1H), 7.46 (dd, J=8.7, 1.8 Hz, 1H), 7.30 (s, 1H), 6.70 (d,J=2.1 Hz, 1H), 6.55 (dd, J=9.0, 2.4 Hz, 1H), 3.90 (brs, 1H), 2.96-2.87(m, 2H), 2.85 (t, J=7.7 Hz, 2H), 1.94-1.79 (m, 3H), 1.03-0.99 (m, 9H).

Example 15:N-isobutyl-6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-amine

Step 1: 4-(4-(5-nitropyridin-2-yl)-1H-pyrazol-1-yl)-2-propylpyridine

A solution of crude2-propyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyridine(3.00 g, 5.3 mmol), 2-Bromo-5-nitropyridine (2.182 g, 10.5 mmol) and 2.0M sodium carbonate (7.902 mL, 15.8 mmol) in DMF (30 mL) was stirred atroom temperature for 5 minutes, then tetrakis(triphenylphosphine)pallladium(0) (130 mg) was then added and the flask was flushed withargon and stirred at 110° C. for overnight. After cooling, the mixturewas partitioned between ethyl acetate (200 mL) and water. The organiclayer was washed with brine, dried over Na₂SO₄ and concentrated. Theresidue was purified by silica gel chromatography (0-60% ethylacetate/hexanes) to afford the desired product as a light yellow solid(1.38 g). ¹H-NMR (300 MHz, CDCl₃): δ 9.44 (d, J=2.1 Hz, 1H), 8.74 (s,1H), 8.65 (d, J=6.0 Hz, 1H), 8.52 (dd, J=9.0, 2.4 Hz, 1H), 8.31 (s, 1H),7.72 (d, J=8.1 Hz, 1H), 7.62 (d, J=1.8 Hz, 1H), 7.53 (dd, J=5.1 and 2.1Hz, 1H), 2.88 (t, J=7.8 Hz, 2H), 1.88-1.80 (m, 2H), 1.02 (t, J=7.8 Hz,3H).

Step 2: 6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-amine

To a suspension of4-(4-(5-nitropyridin-2-yl)-1H-pyrazol-1-yl)-2-propylpyridine (1.380 g,4.5 mmol) in Ethanol (100 mL), was added Tin(II) chloride (2.791 g, 14.7mmol) followed by concentrated hydrogen chloride (6 mL), and thereaction was heated to 80° C. for 6 hrs to give a yellow solution. Afterthe reaction had cooled to ambient temperature, it was poured into anice-cold solution of 10.0 g potassium hydroxide in 100 mL of water anddiluted with 75 mL of ethyl acetate, the layers separated, and theaqueous layer was extracted with ethyl acetate (3×30 mL). The combinedorganics were dried over sodium sulfate and concentrated. The residuewas purified by silica gel chromatography (0-15%methanol/dichloromethane) to afford the desired product as a yellowsolid. ¹H-NMR (300 MHz, CDCl₃): δ 8.57 (d, J=6.0 Hz, 1H), 8.14 (s, 1H),7.97 (s, 1H), 7.55 (s, 1H), 7.44 (dd, J=5.4 and 1.8 Hz, 1H), 7.37 (d,J=8.7 Hz, 2H), 6.75 (d, J=8.1 Hz, 2H), 3.75 (bs, 2H), 2.85 (t, J=7.7 Hz,2H), 1.87-1.79 (m, 2H), 1.02 (t, J=7.4 Hz, 3H).

Step 3: 4-(4-(5-nitropyridin-2-yl)-1H-pyrazol-1-yl)-2-propylpyridine

To a solution of6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-amine (0.080 g,0.3 mmol) in dichloroethane (5 mL) was added isobutyraldehyde (31 μL,0.3 mmol), acetic acid (25 μL, 0.4 mmol) and sodiumtriacetoxyborohydride (0.181 g, 0.9 mmol). The reaction was stirred atroom temperature for 4 hours. The mixture was diluted with saturatedsodium bicarbonate and dichloromethane. The organic layer was washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated. The residue was purified by silica gel chromatography(0-50% ethyl acetate/hexanes). The title compound was obtained as anoff-white solid (59 mg, 61.4%). LC/MS: 336.2 [M+1]⁺; ¹H NMR (300 MHz,CDCl₃): δ 8.57 (d, J=5.4 Hz, 1H), 8.45 (s, 1H), 8.12 (s, 1H), 8.04 (d,J=2.7 Hz, 1H), 7.58 (s, 1H), 7.48 (dd, J=6.0 and 1.8 Hz, 1H), 7.38 (d,J=8.1 Hz, 1H), 6.93 (dd, J=9.0 and 3.0 Hz, 1H), 3.86 (brs, 1H), 3.00 (t,J=5.6 Hz, 2H), 2.84 (t, J=7.7 Hz, 2H), 1.96-1.79 (m, 3H), 1.04-0.98 (m,9H).

Example 16:N-(cyclopropylmethyl)-6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-amine

To a solution of6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-amine (0.080 g,0.3 mmol) in dichloroethane (5 mL) was added 95.0%cyclopropanecarbaldehyde (27 μL, 0.3 mmol), acetic acid (25 μL, 0.4mmol) and sodium triacetoxyborohydride (0.181 g, 0.9 mmol). The reactionwas stirred at room temperature for 4 hours. The mixture was dilutedwith saturated sodium bicarbonate and DCM. The organic layer was washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated. The residue was purified by silica gel chromatography(0-50% ethyl acetate/hexanes). The title compound was obtained as alight yellow solid (39 mg, 40.8%). LC/MS: 334.2 [M+1]⁺; ¹H NMR (300 MHz,CDCl₃): δ 8.57 (d, J=6.0 Hz, 1H), 8.46 (s, 1H), 8.12 (s, 1H), 8.05 (d,J=2.7 Hz, 1H), 7.58 (s, 1H), 7.47 (d, J=5.7 Hz, 1H), 7.38 (d, J=8.7 Hz,1H), 6.93 (dd, J=9.0 and 3.0 Hz, 1H), 3.86 (brs, 1H), 3.02 (d, J=7.2 Hz,2H), 2.84 (t, J=7.7 Hz, 2H), 1.86-1.78 (m, 2H), 1.17-1.09 (m, 1H), 1.01(t, J=7.2 Hz, 3H), 0.64-0.58 (m, 2H), 0.32-0.27 (m, 2H).

Example 17:3-chloro-N-(cyclopropylmethyl)-4-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)aniline

To a solution of3-chloro-4-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)aniline (0.088 g,0.3 mmol) in dichloroethane (5 mL) was added 95.0%cyclopropanecarbaldehyde (26 μL, 0.3 mmol), acetic acid (24 μL, 0.4mmol) and sodium triacetoxyborohydride (0.178 g, 0.8 mmol). The reactionwas stirred at room temperature for 4 hours. The mixture was dilutedwith saturated sodium bicarbonate and dichloromethane. The organic layerwas washed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated. The residue was purified by silica gel chromatography(0-50% ethyl acetate/hexanes). The title compound was obtained as awhite solid (40 mg, 38.5%). LC/MS: 367.2 [M+1]⁺; ¹H NMR (300 MHz,CDCl₃): δ 8.57 (d, J=6.0 Hz, 1H), 8.30 (s, 1H), 7.99 (s, 1H), 7.56 (s,1H), 7.46 (d, J=5.1 Hz, 1H), 7.29 (d, J=8.7 Hz, 1H), 6.71 (s, 1H), 6.57(d, J=8.7 Hz, 1H), 3.98 (brs, 1H), 2.99 (d, J=6.6 Hz, 2H), 2.85 (t,J=7.7 Hz, 2H), 1.89-1.77 (m, 2H), 1.12-1.08 (m, 1H), 1.01 (t, J=7.2 Hz,3H), 0.62-0.57 (m, 2H), 0.30-0.25 (m, 2H).

Example 18:N-(6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)cyclopropanesulfonamide

A solution of6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-amine (0.075 g,0.3 mmol) and Pyridine (65 μL, 0.8 mmol) in Dichloromethane (5 mL) wascooled to 0° C. Then, Cyclopropanesulfonyl chloride (82 μL, 0.8 mmol)was added and reaction mixture was allowed to warm to room temperatureovernight to give a yellow suspension. The reaction mixture was quenchedwith saturated sodium bicarbonate. The layers were separated, and theaqueous layer was extracted with dichloromethane (2×20 mL). The combinedorganics were dried over Na₂SO₄ and concentrated. The residue waspurified by silica gel chromatography (0-50% ethyl acetate/hexanes). Thetitle compound was obtained as a light yellow solid (51 mg, 49.5%).LC/MS: [M+1]⁺, 384.1; ¹HNMR (300 MHz, CDCl₃): δ 8.60 (d, J=6.0 Hz, 1H),8.57 (s, 1H), 8.46 (s, 1H), 8.19 (s, 1H), 7.77 (d, J=5.4 Hz, 1H),7.59-7.48 (m, 3H), 6.38 (brs, 1H), 2.85 (t, J=7.5 Hz, 2H), 2.53-2.49 (m,1H), 1.86-1.79 (m, 2H), 1.22-1.18 (m, 2H), 1.04-0.98 (m, 5H).

Example 19:1-cyclopropyl-N-(6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)methanesulfonamide

A solution of6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-amine (0.075 g,0.3 mmol) and Pyridine (65 μL, 0.8 mmol) in Dichloromethane (5 mL) wascooled to 0° C. Then, cyclopropylmethanesulfonyl chloride (91 mg, 0.6mmol) was added and reaction mixture was allowed to warm to roomtemperature overnight to give a reddish brown suspension. The reactionmixture was quenched with saturated sodium bicarbonate. The layers wereseparated, and the aqueous layer was extracted with dichloromethane(2×20 mL). The combined organics were dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel chromatography(0-50% ethyl acetate/hexanes). The title compound was obtained as anoff-white solid (29 mg, 27.1%). LC/MS: [M+1]⁺, 398.1; ¹HNMR (300 MHz,CDCl₃): δ 8.61 (d, J=6.0 Hz, 1H), 8.56 (s, 1H), 8.42 (s, 1H), 8.19 (s,1H), 7.78 (d, J=1.5 Hz, 1H), 7.60-7.49 (m, 3H), 6.51 (brs, 1H), 3.09 (d,J=6.9 Hz, 2H), 2.86 (t, J=7.7 Hz, 2H), 1.87-1.79 (m, 2H), 1.20-1.18 (m,1H), 1.02 (t, J=7.2 Hz, 3H), 0.75-0.72 (m, 2H), 0.37-0.35 (m, 2H).

Example 20:N-(6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)methanesulfonamide

A round bottom flask was charged with6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-amine (0.100 g,0.4 mmol), dichloromethane (5 mL) and Pyridine (0.087 mL, 1.1 mmol) andthe reaction mixture cooled to 0° C. Methanesulfonyl chloride (0.083 mL,1.1 mmol) was slowly added under nitrogen and the reaction mixture wasstirred at 0° C. for 30 minutes. The mixture was allowed to warm to roomtemperature and stirred for additional 3 hours. The mixture was dilutedwith saturated sodium bicarbonate and dichloromethane. The organic layerwas washed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated. The residue was purified by silica gel chromatography(0-70% ethyl acetate/hexanes). The title compound was obtained as anoff-white solid (56 mg, 43.8%). LC/MS: [M+1]⁺, 358.1; ¹HNMR (300 MHz,CDCl3), δ 8.61 (d, J=5.4 Hz, 1H), 8.57 (s, 1H), 8.45 (s, 1H), 8.21 (s,1H), 7.76 (dd, J=9.0 and 3.0 Hz, 1H), 7.61-7.50 (m, 3H), 6.46 (brs, 1H),3.09 (s, 3H), 2.86 (t, J=7.7 Hz, 2H), 1.87-1.80 (m, 2H), 1.02 (t, J=7.4Hz, 3H).

Example 21:N-isopropyl-6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-amine

To a solution of6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-amine (0.080 g,0.3 mmol) in dichloroethane (10 mL) was added acetone (105 μL, 1.4mmol), acetic acid (25 μL, 0.4 mmol) and sodium triacetoxyborohydride(0.181 g, 0.9 mmol). The reaction was stirred at room temperatureovernight. The reaction mixture partitioned between dichloromethane andsaturated sodium bicarbonate solution. The layers were separated and theaqueous layer was extracted twice with dichloromethane. The combinedorganics were dried over MgSO₄. The residue was purified by silica gelchromatography (0-60% ethyl acetatehexanes). The title compound wasobtained as an off-white solid (30 mg, 32.1%). LC/MS: 322.2 [M+1]⁺; ¹HNMR (300 MHz, CDCl₃): δ 8.57 (d, J=6.0 Hz, 1H), 8.45 (d, J=2.4 Hz, 1H),8.12 (s, 1H), 8.02 (s, 1H), 7.59 (s, 1H), 7.48 (d, J=6.0, 1H), 7.39 (d,J=8.1, 1H), 6.94-6.91 (m, 1H), 3.70-3.66 (m, 2H), 2.84 (t, J=7.7 Hz,2H), 1.86-1.76 (m, 2H), 1.27 (d, J=6.0 Hz, 6H), 1.01 (t, J=7.4 Hz, 3H).

Example 22:1,1,1-trifluoro-N-(6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)methanesulfonamide

Pyridine (0.087 mL, 1.1 mmol) was added dropwise to a solution oftriflic anhydride (0.181 mL, 1.1 mmol) at 0° C. under nitrogen indichloromethane (5 mL) over 10 minutes. The reaction mixture was stirredat the same temperature for 30 minutes. A solution of6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-amine (0.100 g,0.4 mmol) in dichloromethane (3 mL) was added dropwise over 20 minutes.The reaction was then allowed to come to room temperature and stirredfor 1 hour. Upon completion, ice water was added and the dichloromethanelayer was separated. The aqueous was extracted with dichloromethane(2×50 mL). The dichloromethane extracts were combined and dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (0-70% ethylacetate/hexanes). The title compound was obtained as a brown solid (55mg, 36.3%). LC/MS: [M+1]⁺, 412.0; ¹HNMR (300 MHz, DMSO-d6): δ 9.31 (s,1H), 8.67 (d, J=6.0 Hz, 1H), 8.45 (s, 1H), 8.24 (s, 1H), 8.03-7.96 (m,2H), 7.74-7.65 (m, 2H), 2.85 (t, J=7.4 Hz, 2H), 1.81-1.73 (m, 2H), 0.94(t, J=7.2 Hz, 3H).

Example 23:N-cyclopentyl-6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-amine

To a solution of6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-amine (0.075 g,0.3 mmol) in dichloroethane (5 mL) was added Cyclopentanone (0.112 mL,1.3 mmol), acetic acid (0.022 mL, 0.4 mmol) and sodiumtriacetoxyborohydride (0.160 g, 0.8 mmol). The reaction was stirred atroom temperature overnight. The mixture was diluted with saturatedsodium bicarbonate and dichloromethane. The organic layer was washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated. The residue was purified by silica gel chromatography(0-60% ethyl acetate/hexanes). The title compound was obtained as anoff-white solid (40 mg, 42.9%). LC/MS: [M+1]⁺, 348.2; ¹HNMR (300 MHz,CDCl3): δ 8.57 (d, J=5.4 Hz, 1H), 8.45 (s, 1H), 8.12 (s, 1H), 8.03 (s,1H), 7.58 (s, 1H), 7.47 (d, J=5.4 Hz, 1H), 7.38 (d, J=8.1 Hz, 1H), 6.93(d, J=7.2 Hz, 1H), 3.84-3.80 (m, 2H), 2.84 (t, J=7.7 Hz, 2H), 2.08-2.04(m, 2H), 1.86-1.50 (m, 8H), 1.01 (t, J=7.2 Hz, 3H).

Example 24:5-chloro-N-isopropyl-6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-amine

Step 1:3-chloro-5-nitro-2-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridine

A solution of crude2-propyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyridine(1.400 g, 2.5 mmol), 2-bromo-3-chloro-5-nitropyridine (1.191 g, 4.9mmol) and 2.0 M sodium carbonate (3.7 mL, 7.4 mmol) in DMF (8 mL) wasstirred at room temperature for 5 minutes, thentetrakis(triphenylphosphine) pallladium(0) (60 mg) was then added andthe flask was flushed with argon and stirred at 110° C. for overnight.After cooling, the mixture was partitioned between ethyl acetate (200mL) and water. The organic layer was washed with brine, dried overNa₂SO₄ and concentrated. The residue was purified by silica gelchromatography (0-40% ethyl acetate/hexanes) to afford the desiredproduct as a yellow solid (0.63 g). LC/MS: [M+1]⁺, 344.1; ¹H-NMR (300MHz, CDCl₃): δ 9.35 (s, 1H), 8.97 (s, 1H), 8.67-8.59 (m, 3H), 7.64 (s,1H), 7.55 (d, J=5.4 Hz, 1H), 2.89 (t, J=7.8 Hz, 2H), 1.89-1.81 (m, 2H),1.03 (t, J=7.8 Hz, 3H).

Step 2:5-chloro-6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-amine

To a yellow suspension of3-chloro-5-nitro-2-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridine(0.630 g, 1.8 mmol) in Ethanol (50 mL), was added Tin(II) chloride(1.147 g, 6.0 mmol) followed by concentrated hydrogen chloride (3 mL),and the reaction was heated to 80° C. for 6 hrs to give a yellowsolution. After the reaction had cooled to ambient temperature, it waspoured into an ice-cold solution of 10.0 g potassium hydroxide in 100 mLof water and diluted with 75 mL of ethyl acetate, the layers separated,and the aqueous layer was extracted with ethyl acetate (3×30 mL). Thecombined organics were dried over sodium sulfate and concentrated toafford the desired product as a yellow solid (0.53 g, 92%). LC/MS:[M+1]⁺, 314.2; ¹H-NMR (300 MHz, CDCl₃): δ 8.64 (s, 1H), 8.58 (d, J=5.1Hz, 1H), 8.41 (s, 1H), 8.05 (d, J=2.4 Hz, 1H), 7.60 (s, 1H), 7.50 (d,J=6.0 Hz, 1H), 7.09 (d, J=2.4 Hz, 1H), 3.85 (bs, 2H), 2.85 (t, J=7.7 Hz,2H), 1.87-1.79 (m, 2H), 1.01 (t, J=7.4 Hz, 3H).

Step 3:5-chloro-N-isopropyl-6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-amine

To a solution of5-chloro-6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-amine(0.065 g, 0.2 mmol) in dichloroethane (10 mL) was added Acetone (76 μL,1.0 mmol), acetic acid (24 μL, 0.4 mmol) and sodiumtriacetoxyborohydride (0.144 g, 0.7 mmol). The reaction was stirred atroom temperature overnight. The reaction mixture partitioned betweendichloromethane and saturated sodium bicarbonate solution. The layerswere separated and the aqueous layer was extracted twice withdichloromethane. The combined organic layers were dried over MgSO₄. Thesolvents were removed and the residue was purified by silica gelchromatography (0-60% ethyl acetate/hexanes). The title compound wasobtained as a yellow solid (49 mg, 66.5%). LC/MS: 356.2 [M+1]⁺; ¹H NMR(300 MHz, CDCl₃): δ 8.61 (s, 1H), 8.58 (d, J=5.4 Hz, 1H), 8.39 (s, 1H),7.95 (d, J=2.4 Hz, 1H), 7.59 (s, 1H), 7.49 (dd, J=5.4 and 1.5 Hz, 1H),6.93 (d, J=3.0 Hz, 1H), 3.74-3.62 (m, 2H), 2.85 (t, J=7.7 Hz, 2H),1.87-1.77 (m, 2H), 1.28 (d, J=6.0 Hz, 6H), 1.01 (t, J=7.4 Hz, 3H).

Example 25:5-chloro-N-cyclopentyl-6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-amine

To a solution of5-chloro-6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-amine(0.065 g, 0.2 mmol) in dichloroethane (5 mL) was added Cyclopentanone(0.092 mL, 1.0 mmol), acetic acid (0.024 mL, 0.4 mmol) and sodiumtriacetoxyborohydride (0.144 g, 0.7 mmol). The reaction was stirred atroom temperature overnight. The mixture was diluted with saturatedsodium bicarbonate and dichloromethane. The organic layer was washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated. The residue was purified by silica gel chromatography(0-60% ethyl acetate/hexanes). The title compound was obtained as anoff-white solid (22 mg, 27.8%). LC/MS: [M+1]⁺, 382.2; ¹HNMR (300 MHz,CDCl3): δ 8.61 (s, 1H), 8.58 (d, J=5.4 Hz, 1H), 8.40 (s, 1H), 7.96 (d,J=1.5 Hz, 1H), 7.59 (s, 1H), 7.49 (d, J=5.4 Hz, 1H), 6.95 (d, J=2.4 Hz,1H), 3.89-3.80 (m, 2H), 2.85 (t, J=7.7 Hz, 2H), 2.09-2.05 (m, 2H),1.87-1.50 (m, 8H), 1.02 (t, J=7.5 Hz, 3H).

Example 26:5-chloro-N-isobutyl-6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-amine

To a solution of5-chloro-6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-amine(0.065 g, 0.2 mmol) in dichloroethane (5 mL) was added isobutyraldehyde(23 μL, 0.2 mmol), acetic acid (24 μL, 0.4 mmol) and sodiumtriacetoxyborohydride (0.144 g, 0.7 mmol). The reaction was stirred atroom temperature for 4 hours. The mixture was diluted with saturatedsodium bicarbonate and dichloromethane. The organic layer was washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated. The residue was purified by silica gel chromatography(0-40% ethyl acetate/hexanes). The title compound was obtained as ayellow solid (41 mg, 53.3%). LC/MS: 370.2 [M+1]⁺; ¹H NMR (300 MHz,CDCl₃): δ 8.61 (s, 1H), 8.58 (d, J=6.0 Hz, 1H), 8.39 (s, 1H), 7.98 (d,J=2.4 Hz, 1H), 7.59 (s, 1H), 7.50 (dd, J=5.7 and 1.5 Hz, 1H), 6.93 (d,J=2.4 Hz, 1H), 3.99-3.95 (m, 1H), 2.98 (t, J=6.3 Hz, 2H), 2.85 (t, J=7.7Hz, 2H), 1.98-1.79 (m, 3H), 1.04-0.99 (m, 9H).

Example 27:5-chloro-N-(cyclopropylmethyl)-6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-amine

To a solution of5-chloro-6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-amine(0.065 g, 0.2 mmol) in dichloroethane (5 mL) was added 95.0%cyclopropanecarbaldehyde (20 μL, 0.2 mmol), acetic acid (24 μL, 0.4mmol) and sodium triacetoxyborohydride (0.144 g, 0.7 mmol). The reactionwas stirred at room temperature for 4 hours. The mixture was dilutedwith saturated sodium bicarbonate and dichloromethane. The organic layerwas washed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated. The residue was purified by silica gel chromatography(0-40% ethyl acetate/hexanes). The title compound was obtained as ayellow solid (62 mg, 81%). LC/MS: 368.2 [M+1]⁺; ¹H NMR (300 MHz, CDCl₃):δ 8.62 (s, 1H), 8.58 (d, J=5.4 Hz, 1H), 8.40 (s, 1H), 7.99 (d, J=3.0 Hz,1H), 7.59 (s, 1H), 7.49 (dd, J=5.1 and 1.5 Hz, 1H), 6.94 (d, J=2.4 Hz,1H), 4.05 (brs, 1H), 3.03-2.99 (m, 2H), 2.85 (t, J=7.7 Hz, 2H),1.87-1.79 (m, 2H), 1.15-1.11 (m, 1H), 1.01 (t, J=7.4 Hz, 3H), 0.66-0.60(m, 2H), 0.33-0.29 (m, 2H).

Example 28:N-(5-chloro-6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)cyclopropanesulfonamide

A solution of5-chloro-6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-amine(0.065 g, 0.2 mmol) and Pyridine (50 μL, 0.6 mmol) in Dichloromethane (7mL) was cooled to 0° C. Then, Cyclopropanesulfonyl chloride (63 μL, 0.6mmol) was added, and reaction mixture was allowed to warm to roomtemperature overnight to give a yellow suspension. The reaction mixturewas quenched with saturated sodium bicarbonate. The layers wereseparated, and the aqueous layer was extracted with dichloromethane(2×20 mL). The combined organics were dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel chromatography(0-50% ethyl acetate/hexanes). The title compound was obtained as anoff-white solid (38 mg, 42.7%). LC/MS: [M+1]⁺, 418.1; ¹HNMR (300 MHz,CDCl₃): δ 8.78 (s, 1H), 8.61 (d, J=5.4 Hz, 1H), 8.50 (s, 1H), 8.41 (s,1H), 7.85 (s, 1H), 7.61 (s, 1H), 7.51 (d, J=4.8 Hz, 1H), 6.50 (brs, 1H),2.87 (t, J=7.7 Hz, 2H), 2.58-2.55 (m, 1H), 1.87-1.80 (m, 2H), 1.29-1.25(m, 2H), 1.10-0.99 (m, 5H).

Example 29:N-(5-chloro-6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-1-cyclopropylmethanesulfonamide

A solution of5-chloro-6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-amine(0.065 g, 0.2 mmol) and Pyridine (50 μL, 0.6 mmol) in Dichloromethane (7mL) was cooled to 0° C. Then, cyclopropylmethanesulfonyl chloride (67mg, 0.4 mmol) was added, and reaction mixture was allowed to warm toroom temperature overnight to give a reddish brown suspension. Thereaction mixture was quenched with saturated sodium bicarbonate. Thelayers were separated, and the aqueous layer was extracted withdichloromethane (2×20 mL). The combined organics were dried over Na₂SO₄and concentrated. The residue was purified by silica gel chromatography(0-50% ethyl acetate/hexanes). The title compound was obtained as anoff-white solid (35 mg, 38.2%). LC/MS: [M+1]⁺, 431.9; ¹HNMR (300 MHz,CDCl₃): δ 8.76 (s, 1H), 8.61 (d, J=5.4 Hz, 1H), 8.48 (s, 1H), 8.36 (d,J=2.4 Hz, 1H), 7.86 (d, J=2.4 Hz, 1H), 7.61 (s, 1H), 7.51 (dd, J=5.4 and1.8 Hz, 1H), 6.71 (brs, 1H), 3.13 (d, J=6.9 Hz, 2H), 2.87 (t, J=7.7 Hz,2H), 1.90-1.78 (m, 2H), 1.27-1.16 (m, 1H), 1.02 (t, J=7.2 Hz, 3H),0.79-0.73 (m, 2H), 0.40-0.35 (m, 2H).

Example 30:N-(5-chloro-6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)methanesulfonamide

A round bottom flask was charged with5-chloro-6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-amine(0.080 g, 0.3 mmol), dichloromethane (7 mL) and Pyridine (0.062 mL, 0.8mmol) and the reaction mixture cooled to 0° C. Methanesulfonyl chloride(0.059 mL, 0.8 mmol) was slowly added under nitrogen and the reactionmixture was stirred at 0° C. for 30 minutes. The mixture was allowed towarm to room temperature and stirred for additional 3 hours. The mixturewas diluted with saturated sodium bicarbonate and dichloromethane. Theorganic layer was washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated. The residue was purified by silicagel chromatography (0-70% ethyl acetate/hexanes). The title compound wasobtained as an off-white solid (75 mg, 75.1%). LC/MS: [M+1]⁺, 392.0;¹HNMR (300 MHz, CDCl3): δ 8.78 (s, 1H), 8.62 (d, J=6.0 Hz, 1H), 8.49 (s,1H), 8.38 (d, J=2.4 Hz, 1H), 7.84 (d, J=2.1 Hz, 1H), 7.61 (d, J=1.8 Hz,1H), 7.51 (dd, J=5.7 and 2.1 Hz, 1H), 6.60 (brs, 1H), 3.13 (s, 3H), 2.87(t, J=7.7 Hz, 2H), 1.88-1.80 (m, 2H), 1.02 (t, J=7.4 Hz, 3H).

Example 31:N-(5-chloro-6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-1,1,1-trifluoromethanesulfonamide

Pyridine (0.054 mL, 0.7 mmol) was added dropwise to a solution oftriflic anhydride (0.113 mL, 0.7 mmol) at 0° C. under nitrogen indichloromethane (5 mL) over 10 minutes. The reaction mixture was stirredat the same temperature for 30 minutes. A solution of5-chloro-6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-amine(0.070 g, 0.2 mmol) in dichloromethane (3 mL) was added dropwise over 20min. The reaction was then allowed to come to room temperature andstirred for 1 hour. Upon completion, ice water was added and thedichloromethane layer was separated. The aqueous was extracted withdichloromethane (2×50 mL). The dichloromethane extracts were combinedand dried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by silica gel chromatography (0-15%methanol/dichlormethane). The title compound was obtained as a brownsolid (17 mg, 16.9%). LC/MS: [M+1]⁺, 445.9; ¹HNMR (300 MHz, DMSO-d6): δ8.80 (s, 1H), 8.62 (d, J=6.0 Hz, 1H), 8.51 (s, 1H), 8.44 (s, 1H), 7.82(s, 1H), 7.63 (s, 1H), 7.54 (d, J=5.1 Hz, 1H), 2.87 (t, J=7.7 Hz, 2H),1.88-1.84 (m, 2H), 1.01 (t, J=7.4 Hz, 3H).

Example 32:N-cyclopentyl-5-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine

To a solution of5-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine (0.080 g,0.3 mmol) in dichloroethane (5 mL) was added Cyclopentanone (0.152 mL,1.7 mmol), acetic acid (0.033 mL, 0.6 mmol) and Sodiumtriacetoxyborohydride (0.181 g, 0.9 mmol). The reaction was stirred atroom temperature overnight. The mixture was diluted with saturatedsodium bicarbonate and dichloromethane. The organic layer was washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated. The residue was purified by silica gel chromatography(0-60% ethyl acetate/hexanes). The title compound was obtained as alight yellow oil (12 mg, 11.5%). LC/MS: [M+1]⁺, 348.1; ¹HNMR (300 MHz,CDCl3): δ 8.58 (d, J=5.4 Hz, 1H), 8.30 (s, 1H), 8.14 (s, 1H), 7.95 (s,1H), 7.64-7.45 (m, 3H), 6.47 (d, J=9.0 Hz, 1H), 4.78 (brs, 1H),4.02-4.01 (m, 1H), 2.85 (t, J=7.7 Hz, 2H), 2.09-2.05 (m, 2H), 1.87-1.50(m, 8H), 1.01 (t, J=7.5 Hz, 3H).

Example 33:N-cyclobutyl-5-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine

To a solution of5-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine (0.080 g,0.3 mmol) in dichloroethane (5 mL) was added cyclobutanone (0.111 mL,1.7 mmol), acetic acid (0.033 mL, 0.6 mmol) and Sodiumtriacetoxyborohydride (0.181 g, 0.9 mmol). The reaction was stirred atroom temperature overnight. The mixture was diluted with saturatedsodium bicarbonate and dichloromethane. The organic layer was washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated. The residue was purified by silica gel chromatography(0-60% ethyl acetate/hexanes). The title compound was obtained as alight yellow solid (26 mg, 26.9%). LC/MS: [M+1]⁺, 334.1; ¹HNMR (300 MHz,CDCl3): δ 8.58 (d, J=5.4 Hz, 1H), 8.31 (s, 1H), 8.14 (s, 1H), 7.95 (s,1H), 7.62-7.56 (m, 2H), 7.45 (d, J=5.7 Hz, 1H), 6.39 (d, J=9.0 Hz, 1H),4.87 (brs, 1H), 4.19-4.12 (m, 1H), 2.85 (t, J=7.7 Hz, 2H), 2.48-2.45 (m,2H), 1.95-1.79 (m, 6H), 1.02 (t, J=7.4 Hz, 3H).

Example 34:5-(3,5-dimethyl-1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)-N-isobutylpyridin-2-amine

Step 1: 4-(4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)-2-propylpyridine

A microwave vial was charged with 4-bromo-2-(n-propyl)pyridine (2.030 g,10.1 mmol), 4-bromo-3,5-dimethylpyrazole (1.776 g, 10.1 mmol), copper(I)iodide (0.386 g, 2.0 mmol), cesium carbonate (9.917 g, 30.4 mmol) andDMA (5 mL) and the reaction mixture heated to 140° C. for 16 hours. Thereaction mixture was cooled to room temperature and diluted with waterand extracted with ethyl acetate (2×100 mL). The organic solvents werewashed with water, brine and dried over MgSO₄. The solvents wereevaporated to dryness and the resultant residue was purified by flashchromatography (0-50% ethyl acetate in hexanes). The collected fractionswere dried to evaporation to give the product as colorless oil (1.25 g,42%)). LC/MS: [M+2]⁺, 296.0; ¹H NMR (300 MHz, CDCl3): δ 8.59 (d, J=5.1Hz, 1H), 7.31 (s, 1H), 7.22 (dd, J=5.4 and 1.8 Hz, 1H), 2.82 (t, 7.5 Hz,2H), 2.43 (s, 3H), 2.30 (s, 3H), 1.83-1.75 (m, 2H), 0.99 (t, J=7.5 Hz,3H).

Step 2:5-(3,5-dimethyl-1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine

A solution of 4-(4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)-2-propylpyridine(0.400 g, 1.4 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.299 g,1.4 mmol) and 2.0 M sodium carbonate (2.039 mL, 4.1 mmol) in DMF (10 mL)was stirred at room temperature for 5 minutes, andtetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.03 mmol) was addedand the flask was degassed and flushed with argon. This process wasrepeated three times and the reaction mixture stirred at 110° C.overnight. After cooling, the mixture was diluted with water andextracted with ethyl acetate (3×50 mL). The combined organic layer waswashed with brine, dried over MgSO₄ and concentrated. The residue waspurified by silica gel chromatography (0-20% dichloromethane inMethanol) to afford the desired product (0.38 g, 73%). LC/MS: [M+1]⁺,308.1; 1H NMR (300 MHz, CDCl3): δ 8.60 (d, J=5.7 Hz, 1H), 7.71-7.31 (m,4H), 6.62 (d, J=8.7 Hz, 1H), 4.53 (bs, 2H), 2.85 (t, J=7.2 Hz, 2H), 2.40(s, 3H), 2.30 (s, 3H), 1.86-1.78 (m, 2H), 1.00 (t, J=6.3 Hz, 3H).

Step 3:5-(3,5-dimethyl-1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)-N-isobutylpyridin-2-amine

To a solution of5-(3,5-dimethyl-1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine(0.095 g, 0.2 mmol) in dichloroethane (5 mL) was added isobutyraldehyde(27 μL, 0.3 mmol), acetic acid (21 μL, 0.4 mmol) and sodiumtriacetoxyborohydride (0.156 g, 0.7 mmol). The reaction was stirred atroom temperature for 4 hours. The mixture was diluted with saturatedsodium bicarbonate and dichloromethane. The organic layer was washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated. The residue was purified by silica gel chromatography(0-50% ethyl acetate/hexanes). The title compound was obtained as awhite oil (29 mg, 31.6%). LC/MS: 364.0 [M+1]⁺; ¹H NMR (300 MHz, CDCl₃):δ 8.59 (d, J=5.7 Hz, 1H), 8.03 (s, 1H), 7.69-7.40 (m, 3H), 6.48 (d,J=8.1 Hz, 1H), 4.76 (bs, 1H), 3.14 (t, J=6.2 Hz, 2H), 2.84 (t, J=7.7 Hz,2H), 2.40 (s, 3H), 2.30 (s, 3H), 1.96-1.79 (m, 3H), 1.04-0.98 (m, 9H).

Example 35:N-(cyclopropylmethyl)-5-(3,5-dimethyl-1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine

To a solution of5-(3,5-dimethyl-1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine(0.095 g, 0.2 mmol) in dichloroethane (5 mL) was addedcyclopropanecarbaldehyde (23 μL, 0.3 mmol), acetic acid (21 μL, 0.4mmol) and sodium triacetoxyborohydride (0.156 g, 0.7 mmol, 3.0 equiv.).The reaction was stirred at room temperature for 4 hours. The mixturewas diluted with saturated sodium bicarbonate and dichloromethane. Theorganic layer was washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated. The residue was purified by silicagel chromatography (0-40% ethyl acetate/hexanes). The title compound wasobtained as a white solid (54 mg, 59.2%). LC/MS: 362.2 [M+1]⁺; ¹H NMR(300 MHz, CDCl₃): δ 8.59 (d, J=5.1 Hz, 1H), 8.03 (d, J=1.8 Hz, 1H),7.71-7.36 (m, 3H), 6.49 (d, J=8.7 Hz, 1H), 4.74 (bs, 1H), 3.19 (t, J=6.2Hz, 2H), 2.84 (t, J=7.7 Hz, 2H), 2.40 (s, 3H), 2.30 (s, 3H), 1.86-1.78(m, 2H), 1.15-1.10 (m, 1H), 1.01 (t, J=7.2 Hz, 3H), 0.60-0.56 (m, 2H),0.32-0.29 (m, 2H).

Example 36:5-(3,5-dimethyl-1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)-N-isopropylpyridin-2-amine

To a solution of5-(3,5-dimethyl-1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine(80% pure by NMR, 0.095 g, 0.2 mmol) in dichloroethane (10 mL) was addedacetone (91 μL, 1.2 mmol), acetic acid (21 μL, 0.4 mmol) and sodiumtriacetoxyborohydride (0.156 g, 0.7 mmol). The reaction was stirred atroom temperature overnight. The reaction mixture partitioned betweendichloromethane and sat'd sodium bicarbonate solution. The layers wereseparated and the aqueous layer was extracted twice withdichloromethane. The combined organics were dried over MgSO₄. Thesolvents were removed and resulting residue was purified by silica gelchromatography (0-60% ethyl acetate/hexanes). The title compound wasobtained as a white oil (26 mg, 28.9%). LC/MS: 350.2 [M+1]⁺; ¹H NMR (300MHz, CDCl₃): δ 8.59 (d, J=5.1 Hz, 1H), 8.02 (s, 1H), 7.71-7.29 (m, 3H),6.46 (d, J=9.0 Hz, 1H), 4.50 (bs, 1H), 3.94-3.88 (m, 1H), 2.85 (t, J=7.7Hz, 2H), 2.40 (s, 3H), 2.30 (s, 3H), 1.86-1.78 (m, 2H), 1.29 (d, J=6.6Hz, 6H), 1.01 (t, J=7.2 Hz, 3H).

Example 37:N-(5-(3,5-dimethyl-1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-yl)methanesulfonamide

A round bottom flask was charged with5-(3,5-dimethyl-1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine(0.060 g, 0.2 mmol), dichloromethane (7 mL) and Pyridine (0.047 mL, 0.6mmol) and the reaction mixture cooled to 0° C. Methanesulfonyl chloride(0.045 mL, 0.6 mmol) was slowly added under nitrogen and the reactionmixture was stirred at 0° C. for 30 minutes. The mixture was allowed towarm to room temperature and stirred for additional 3 hours. The mixturewas diluted with saturated sodium bicarbonate and dichloromethane. Theorganic layer was washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated. The residue was purified by silicagel chromatography (0-70% ethyl acetate/hexanes). The title compound wasobtained as an off-white solid (14 mg, 17.7%). LC/MS: [M+1]⁺, 386.1;¹HNMR (300 MHz, CDCl3): δ 8.63 (d, J=5.1 Hz, 1H), 8.25 (s, 1H), 7.67(dd, J=8.4, 2.1 Hz, 1H), 7.36-7.30 (m, 3H), 3.26 (s, 3H), 2.86 (t, J=7.7Hz, 2H), 2.42 (s, 3H), 2.33 (s, 3H), 1.86-1.78 (m, 2H), 1.01 (t, J=7.4Hz, 3H).

Example 38:N-cyclobutyl-5-(3,5-dimethyl-1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine

To a solution of5-(3,5-dimethyl-1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine(0.070 g, 0.2 mmol) in dichloroethane (5 mL) was added cyclobutanone(0.172 mL, 2.3 mmol), acetic acid (0.039 mL, 0.7 mmol) and Sodiumtriacetoxyborohydride (0.288 g, 1.4 mmol). The reaction was stirred atroom temperature overnight. The mixture was diluted with saturatedsodium bicarbonate and dichloromethane. The organic layer was washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated. The residue was purified by silica gel chromatography(0-60% ethyl acetate/hexanes). The title compound was obtained as alight yellow solid (35 mg, 41%). LC/MS: [M+1]⁺, 362.3; ¹HNMR (300 MHz,CDCl3): δ 8.59 (d, J=5.7 Hz, 1H), 8.01 (s, 1H), 7.40-7.37 (m, 3H), 6.42(d, J=9.0 Hz, 1H), 4.19-4.16 (m, 1H), 2.84 (t, J=7.7 Hz, 2H), 2.48-2.45(m, 2H), 2.40 (s, 3H), 2.30 (s, 3H), 1.94-1.78 (m, 6H), 1.01 (t, J=7.2Hz, 3H).

Example 39:N-(5-(3,5-dimethyl-1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-yl)-1,1,1-trifluoromethanesulfonamide

Pyridine (0.062 mL, 0.8 mmol) was added dropwise to a solution oftriflic anhydride (0.129 mL, 0.8 mmol) at 0° C. under nitrogen indichloromethane (5 mL) over 10 minutes. The reaction mixture was stirredat the same temperature for 30 minutes. A solution of5-(3,5-dimethyl-1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine(0.080 g, 0.3 mmol) in dichloromethane (3 mL) was added dropwise over 20minutes. The reaction was then allowed to come to room temperature andstirred for 1 hour. Upon completion, ice water was added and thedichloromethane layer was separated. The aqueous was extracted withdichloromethane (2×50 mL). The dichloromethane extracts were combinedand dried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by silica gel chromatography (0-15%methanol/dichloromethane). The title compound was obtained as a brownsolid (53 mg, 44.1%). LC/MS: [M+1]⁺, 440.2; ¹HNMR (300 MHz, CDCl3): δ8.66 (d, J=5.4 Hz, 1H), 8.23 (s, 1H), 7.98 (s, 2H), 7.37-7.30 (m, 2H),2.88 (t, J=7.7 Hz, 2H), 2.45 (s, 3H), 2.36 (s, 3H), 1.87-1.80 (m, 2H),1.02 (t, J=7.4 Hz, 3H).

Example 40:N-cyclopentyl-5-(3,5-dimethyl-1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine

To a solution of5-(3,5-dimethyl-1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine(0.080 g, 0.2 mmol) in dichloroethane (5 mL) was added Cyclopentanone(0.184 mL, 2.1 mmol), acetic acid (0.036 mL, 0.6 mmol) and sodiumtriacetoxyborohydride (0.264 g, 1.2 mmol). The reaction was stirred atroom temperature overnight. The mixture was diluted with saturatedsodium bicarbonate and dichloromethane. The organic layer was washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated. The residue was purified by silica gel chromatography(0-60% ethyl acetate/hexanes). The title compound was obtained as alight oil (17 mg, 21.2%). LC/MS: [M+1]⁺, 376.3; ¹HNMR (300 MHz, CDCl3):δ 8.59 (d, J=5.7 Hz, 1H), 8.02 (s, 1H), 7.40-7.31 (m, 3H), 6.50 (d,J=8.1 Hz, 1H), 4.82 (s, 1H), 4.03-3.98 (m, 1H), 2.85 (t, J=7.7 Hz, 2H),2.40 (s, 3H), 2.30 (s, 3H), 2.10-2.07 (m, 2H), 1.86-1.65 (m, 8H), 1.01(t, J=7.2 Hz, 3H).

Example 41:N-(tert-butyl)-5-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine

A solution of2-propyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyridine(80% pure by LC/MS, 0.100 g, 0.3 mmol),5-bromo-N-(tert-butyl)pyrimidin-2-amine (0.090 g, 0.4 mmol) and sodiumcarbonate (0.383 mL, 0.8 mmol) in DMF (6 mL) was stirred at roomtemperature for 5 minutes, then tetrakis(triphenylphosphine)pallladium(0) (10 mg) was then added and the flask was flushed withargon and stirred at 110° C. for overnight. The reaction mixturepartitioned between dichloromethane and saturated sodium bicarbonatesolution. The layers were separated and the aqueous layer was extractedtwice with dichloromethane. The combined organics were dried over MgSO₄.The solvents were removed and resulting residue was purified by silicagel chromatography (0-30% ethyl acetate/hexanes) two times. The titlecompound was obtained as a yellow solid (16 mg, 18.5%). LC/MS: 337.3[M+1]⁺; ¹H NMR (300 MHz, CDCl₃): δ 8.60 (d, J=5.1 Hz, 1H), 8.47 (s, 2H),8.16 (s, 1H), 7.94 (s, 1H), 7.56 (d, J=1.8 Hz, 1H), 7.45 (dd, J=5.4 and1.8 Hz, 1H), 5.24 (brs, 1H), 2.86 (t, J=7.7 Hz, 2H), 1.87-1.80 (m, 2H),1.45 (s, 9H), 1.02 (t, J=7.2 Hz, 3H).

Example 42:N-isopropyl-5-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine

A solution of2-propyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyridine(80% pure by LC/MS 0.100 g, 0.3 mmol),5-bromo-N-isopropylpyrimidin-2-amine (0.084 g, 0.4 mmol) and 2.0 Msodium carbonate (0.383 mL, 0.8 mmol) in DMF (6 mL) was stirred at roomtemperature for 5 minutes, then tetrakis(triphenylphosphine)pallladium(0) (10 mg) was then added and the flask was flushed withargon and stirred at 110° C. for overnight. The reaction mixturepartitioned between dichloromethane and saturated sodium bicarbonatesolution. The layers were separated and the aqueous layer was extractedtwice with dichloromethane. The combined organics were dried over MgSO₄.The solvents were removed and resulting residue was purified by silicagel chromatography (0-30% ethyl acetate/hexanes) two times. The titlecompound was obtained as a yellow solid (32 mg, 38.1%). LC/MS: 323.3[M+1]⁺; ¹H NMR (300 MHz, CDCl₃): δ 8.60 (d, J=5.1 Hz, 1H), 8.48 (s, 2H),8.16 (s, 1H), 7.94 (s, 1H), 7.71-7.45 (m, 2H), 5.05 (bs, 1H), 4.21-4.14(m, 1H), 2.86 (t, J=7.7 Hz, 2H), 1.87-1.77 (m, 2H), 1.28 (d, J=6.3 Hz,6H), 1.02 (t, J=7.2 Hz, 3H).

Example 43:N-cyclopentyl-5-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine

A solution of2-propyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyridine(80% pure by LC/MS 0.100 g, 0.3 mmol),5-bromo-N-cyclopentylpyrimidin-2-amine (0.090 g, 0.4 mmol) and 2.0 Msodium carbonate (0.383 mL, 0.8 mmol) in DMF (6 mL) was stirred at roomtemperature for 5 minutes, then tetrakis(triphenylphosphine)pallladium(0) (10 mg) was then added and the flask was flushed withargon and stirred at 110° C. for overnight. The reaction mixturepartitioned between dichloromethane and sat'd sodium bicarbonatesolution. The layers were separated and the aqueous layer was extractedtwice with dichloromethane. The combined organics were dried over MgSO₄.The solvents were removed and resulting residue was purified by silicagel chromatography (0-60% ethyl acetate/hexanes) two times. The titlecompound was obtained as a yellow solid (73 mg, 79.6%). LC/MS: 349.3[M+1]⁺; ¹H NMR (300 MHz, CDCl₃): δ 8.60 (d, J=5.7 Hz, 1H), 8.48 (s, 2H),8.16 (s, 1H), 7.94 (s, 1H), 7.71-7.46 (m, 2H), 5.19 (bs, 1H), 4.32-4.29(m, 1H), 2.86 (t, J=7.7 Hz, 2H), 2.11-2.06 (m, 2H), 1.87-1.68 (m, 6H),1.53-1.50 (m, 2H), 1.02 (t, J=7.2 Hz, 3H).

Example 44:5-(4-(6-(isopropylamino)pyridin-3-yl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one

Step 1: 5-bromo-1-propylpyridin-2(1H)-one

A round bottom flask was charged with 2-hydroxy-5-bromopyridine (1.000g, 5.7 mmol), 1-iodopropane (2.81 mL, 28.7), potassium carbonate (3.972g, 28.7 mmol) and tween 80 (2% w/w in water, 10 mL) and the reactionmixture was heated to 70° C. overnight. The reaction mixture was dilutedwith water and extracted with ethyl acetate (3×50 mL) and the combinedorganics were washed with brine and dried over MgSO₄. The solvents wereevaporated to dryness and the residue purified by flash chromatography(silica gel, 0-50% ethyl acetate in hexanes). The desired fractions wereevaporated to dryness to give the compound as colorless oil. LC/MS: [M⁺]and [M+2]⁺ 216.1 and 218.1; ¹H NMR (300 MHz, DMSO-d6): δ 8.00 (d, J=2.7Hz, 1H), 7.49 (dd, J=9.9 and 3.0 Hz, 1H), 6.34 (d, J=10.2 Hz, 1H), 3.79(t, J=6.9 Hz, 2H), 1.64-1.57 (m, 2H), 0.82 (t, J=7.5 Hz, 3H).

Step 2: 5-(4-bromo-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one

To a stirred solution of 5-bromo-1-propylpyridin-2(1H)-one (1.029 g, 4.8mmol), cesium carbonate (4.655 g, 14.3 mmol), 3-bromopyrazole (0.700 g,4.8 mmol), in anhydrous DMA (3 mL) under argon was added and copper(I)iodide (0.181 g, 1.0 mmol). The mixture was stirred at 120° C.overnight. After cooling, the mixture was diluted with water andextracted with ethyl acetate (3×20 mL). The combined organics werewashed with brine and dried over MgSO₄. The solvents were dried toevaporation and the residue purified by flash chromatography (0-100%ethyl acetate in hexanes). The pure fractions were collected and driedto give the product as a liquid (320 mg, 24%). LC/MS: [M+1]⁺ 282.1; ¹HNMR (300 MHz, CDCl₃): δ 8.25 (d, J=2.4 Hz, 1H), 7.84-7.76 (m, 2H), 7.66(dd, J=9.9 and 2.4 Hz, 1H), 7.56 (dd, J=8.7 and 2.4 Hz, 1H) 6.68 (d,J=9.9 Hz, 1H), 6.55 (d, J=8.1 Hz, 1H), 4.51 (bs, 2H), 3.96 (t, J=7.8 Hz,2H), 1.87-1.80 (m, 2H), 0.99 (t, J=7.5 Hz, 3H).

Step 3:5-(4-(6-aminopyridin-3-yl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one

A microwave vial was charged with5-(4-bromo-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one (0.300 g, 1.1mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine(0.278 g, 1.3 mmol), potassium carbonate (0.525 g, 3.8 mmol), dioxan (12mL) and water (3 mL) and the flask was degassed and flushed with argon.PdCl₂(dppf) (0.104 g, 0.1 mmol) was added and the reaction flask wasagain degassed and flushed with argon. The reaction mixture was thenheated to 100° C. for 45 minutes in a microwave. The reaction was cooledto room temperature and quenched with sat. NaHCO₃ and extracted withethyl acetate (3×40 mL). The combined organics were washed with water,brine and dried over MgSO₄. The solvents were evaporated to dryness andthe residue purified by flash chromatography (silica gel, 0-60% ethylacetates in hexanes) to give the product as a brown oil (220 mg, 70%).LC/MS: [M+1]⁺ 296.2; ¹H NMR (300 MHz, CDCl₃): δ 8.26 (d, J=1.8 Hz, 1H),7.83 (d, J=5.1 Hz, 2H), 7.76 (d, J=3.0 Hz, 1H), 7.66 (dd, J=9.9 and 3.0Hz, 1H), 7.57 (8.7 and 2.4 HZ, 1H), 6.68 (d, J=9.3 Hz, 1H), 6.56 (d,J=8.7 Hz, 1H), 4.49 (s, 2H), 3.97 (t, J=7.2 Hz, 2H), 1.88-1.80 (m, 2H),1.00 (t, J=6.9 Hz, 3H).

Step 4:5-(4-(6-(isopropylamino)pyridin-3-yl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one

A round bottom flask was charged with5-(4-(6-aminopyridin-3-yl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one(0.140 g, 0.5 mmol), acetone (0.171 mL, 2.4 mmol.), acetic acid (0.040mL, 0.7 mmol), sodium triacetoxyborohydride (0.500 g, 2.4 mmol) and1,2-dichloroethane (5 mL). The reaction was stirred at 40° C. underargon for 30 minutes. The reaction mixture was cooled and quenched withsaturated NaHCO₃ (10 mL) and extracted with dichloromethane (3×50 mL).The combined organics were washed with the water, brine and dried overMgSO₄. The solvents were evaporated under reduced pressure to drynessand the residue purified by flash chromatography (silica gel, 0-20%methanol in dichloromethane) to afford the product as tan colored solid(19 mg, 12%). LC/MS: 338.2 [M+1]⁺; ¹H NMR (300 MHz, CDCl₃): δ 8.26 (d,J=1.8 Hz, 1H), 7.83-7.75 (m, 3H), 7.66 (dd, J=9.9 & 3.0 Hz, 1H), 7.54(dd, J=8.7 & 3.0 Hz, 1H), 6.68 (d, J=9.9 Hz, 1H), 6.41 (d, J=8.7 Hz,1H), 4.44 (d, J=8.1 Hz, 1H), 3.99-3.87 (m, 3H), 1.88-1.62 (m, 2H), 1.26(d, J=6.6 Hz, 6H), 1.00 (t, J=6.9 Hz, 3H).

Example 45:N-(4-(1-(6-oxo-1-propyl-1,6-dihydropyridin-3-yl)-1H-pyrazol-4-yl)phenyl)methanesulfonamide

Step 1: 5-(4-(4-nitrophenyl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one

A microwave vial was charged with5-(4-bromo-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one (0.300 g, 1.1mmol), 4-Nitrophenylboronic acid (0.177 g, 1.1 mmol,), potassiumcarbonate (0.441 g, 3.2 mmol), dioxan (12 mL) and water (3 mL) and theflask was degassed and flushed with argon. PdCl₂(dppf) (0.104 g, 0.1mmol) was added and the reaction flask was again degassed and flushedwith argon. The reaction mixture was then heated to 100° C. for 45minutes in a microwave. The reaction was cooled to room temperature andquenched with sat. NaHCO₃ and extracted with ethyl acetate (3×20 mL).The combined organics were washed with water, brine and dried overMgSO₄. The solvents were evaporated to dryness and the residue purifiedby flash chromatography (silica gel, 0-100% ethyl acetates in hexanes)to give the product as a solid (320 mg, 93%). LC/MS: [M+1]⁺ 325.1; ¹HNMR (300 MHz, CDCl₃): δ 8.28-8.25 (m, 2H), 8.03 (d, J=3.6 Hz, 2H), 7.81(d, J=2.4 Hz, 1H), 7.69-7.65 (m, 3H), 6.70 (d, J=9.9 Hz, 1H), 3.980 (t,J=7.5 Hz, 2H), 1.89-1.81 (m, 2H), 1.01 (t, J=7.5 Hz, 3H).

Step 2: 5-(4-(4-aminophenyl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one

A round bottom flask was charged with5-(4-(4-nitrophenyl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one (0.345g, 1.2 mmol), ethanol (20 mL) and Tin(II) chloride (0.666 g, 3.5 mmol)was added and the reaction mixture heated to 85° C. for 45 minutes. Thereaction mixture was cooled and poured into 50 mL of 2M KOH. This wasextracted with ethyl acetate (3×50 mL). The combined organics werewashed with brine and dried over MgSO₄. The solvents were evaporated togive the product as pale brown solid which was used in the next reactionwithout further purification (290 mg, 93%). LC/MS: 295.2 [M+1]⁺; ¹H NMR(300 MHz, CDCl₃): δ 7.84 (s, 1H), 7.78 (s, 1H), 7.75 (d, J=3.0 Hz, 1H),7.65 (dd, J=9.9 and 3.0 Hz, 1H), 7.39-7.29 (m, 2H), 6.74-6.66 (m, 3H),3.96 (t, J=7.5 Hz, 2H), 1.88-1.80 (m, 2H), 0.99 9t, J=6.9 Hz, 3H).

Step 3:N-(4-(1-(6-oxo-1-propyl-1,6-dihydropyridin-3-yl)-1H-pyrazol-4-yl)phenyl)methanesulfonamide

A round bottom flask was charged with5-(4-(4-aminophenyl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one (0.120g, 0.4 mmol), dichloromethane (4 mL) and Pyridine (0.148 mL, 1.8 mmol)and methanesulfonyl chloride (0.142 mL, 1.8 mmol) were added at 0° C.under argon. The reaction mixture was stirred at that temperature for 30minutes. The reaction was quenched with sat. NaHCO₃ and extracted withdichloromethane (3×50 mL). The combined organics were washed with water,brine and dried over MgSO₄. The solvents were evaporated to dryness andthe residue was purified by flash chromatography (silica gel, 0-100%ethyl acetate in hexanes) to give the product as tan colored solid (26mg, 19%). LC/MS: 373.1 [M+1]⁺; ¹H NMR (300 MHz, CDCl₃): δ 7.91 (d, J=6.0Hz, 2H), 7.79 (d, J=2.7 Hz, 1H), 7.67 (dd, J=9.9 & 3.0 Hz, 1H), 7.52 (d,J=9.0 Hz, 2H), 7.27 (1H), 6.71 (d, J=9.9 Hz, 1H), 6.37 (s, 1H), 3.98 (t,J=6.9 Hz, 2H), 3.05 (s, 3H), 1.90-1.83 (m, 2H), 1.02 (t, J=6.9 Hz, 3H).

Example 46:N-(4-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)phenyl)methanesulfonamide

Step 1: 4-bromo-1-(3-(trifluoromethyl)phenyl)-1H-pyrazole

To a stirred mixture of m-bromobenzotrifluoride (0.500 g, 2.2 mmol),3-bromopyrazole (0.327 g, 2.2 mmol), potassium carbonate (0.921 g, 6.7mmol,) in anhydrous toluene (3 mL) under argon were addedtrans-N,N′-dimethyl-1,2-cyclohexanediamine (0.035 mL, 0.2 mmol) andcopper(I) iodide (0.021 g, 0.1 mmol,). The mixture was stirred at 120°C. for 2 hours. The reaction mixture was cooled to room temperature andquenched with water and extracted with ethyl acetate (3×25 mL). Thecombined organics were washed with brine and dried over MgSO₄. Thesolvents were evaporated to dryness and the residue purified by flashchromatography (silica gel, 0-60% ethyl acetate in hexane) to afford theproduct as colorless oil (0.13 g, 20%). ¹H NMR (300 MHz, CDCl₃): δ 7.99(s, 1H), 7.94 (s, 1H), 7.84-7.82 (m, 1H), 7.70 (s, 1H), 7.61-7.56 (m,2H).

Step 2:N-(4-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)phenyl)methanesulfonamide

A microwave vial was charged with4-bromo-1-(3-(trifluoromethyl)phenyl)-1H-pyrazole (0.130 g, 0.4 mmol),N-4-methanesulfonamidephenylboronic acid (0.096 g, 0.4 mmol), dioxan (8mL) and water (2 mL) and the flask was degassed and flushed with argon.PdCl₂(dppf) (0.037 g, 0.04 mmol.) was added and the reaction flask wasagain degassed and flushed with argon. The reaction mixture was thenheated to 100° C. in a microwave for 45 minutes. The reaction was cooledto room temperature and quenched with sat. NaHCO₃ and extracted withethyl acetate (3×50 mL). The combined organics were washed with water,brine and dried over MgSO₄. The solvents were evaporated to dryness andthe residue purified by flash chromatography (silica gel, 0-60% ethylacetate in hexane) to afford the product as white solid (125 mg, 73%).LC/MS: [M+1]⁺ 382.0; ¹H NMR (300 MHz, CDCl₃): δ 8.18 (s, 1H), 8.02 (s,1H), 7.99 (s, 1H), 7.94 (d, J=8.1 Hz, 1H), 7.65-7.55 (m, 4H), 7.30-7.26(m, 2H), 6.40 (s, 1H)m 3.04 (s, 3H).

Using the procedure of Example 46 and commercially available arylbromides in place of m-bromobenzotrifluoride for step 1 of Example 46,the following examples were prepared.

Ex. No. Name Structure Analytical data 47 N-(4-(1-(3-propylphenyl)-1H-pyrazol-4-yl)phenyl) methanesulfonamide

LC/MS: 356.1 [M + 1]⁺; ¹H NMR (300 MHz, CDCl₃): δ 8.14 (s, 1H), 7.96 (s,1H0, 7.58-7.50 (s, 4H), 7.38 (t, J = 8.1 Hz, 1H), 7.27-7.25 (m, 2H),7.14 (d, J = 8.4 Hz, 1H), 6.33 (bs, 1H), 3.04 (s, 3H), 2.67 (t, J = 7.8Hz, 2H), 1.75-1.67 (m, 2H), 0.97 (t, J = 7.5 Hz, 3H). 48 N-(4-(1-(3-(difluoromethyl)phenyl)- 1H-pyrazol-4-yl)phenyl) methanesulfonamide

LC/MS: 364.1 [M + 1]⁺; ¹H NMR (300 MHz, CDCl₃): δ 8.18 (s, 1H), 7.99 (s,1H), 7.91 (s, 1H, 7.86 (d, J = 8.1 Hz, 1H), 7.61-7.54 (m, 3H), 7.47-7.44 (m, 1H), 7.29 (s, 1H), 6.72 (t, J = 56.1 Hz, 1H), 6.42 (s, 1H),3.05 (s, 3H). 49 N-(4-(1-(3-(piperidin-1- yl)phenyl)-1H-pyrazol-4-yl)phenyl) methanesulfonamide

LC/MS: 397.2 [M + 1]⁺; ¹H NMR (300 MHz, CDCl₃): δ 8.11 (s, 1H), 7.94 (s,1H), 7.55 (d, J = 8.1 Hz, 2H), 7.33- 7.24 (m, 4H), 7.06 (d, J = 6.9 Hz,1H), 6.87 (dd, J = 8.4 and 2.4 Hz, 1H), 6.36 (s, 1H), 3.26 (t, J = 4.8Hz, 4H), 3.03 (s, 3H), 1.76-1.71 (m, 4H), 1.62-1.60 (m, 2H). 50N-(4-(1-(3-isopropylphenyl)- 1H-pyrazol-4-yl)phenyl) methanesulfonamide

LC/MS: 356.1 [M + 1]⁺; ¹H NMR (300 MHz, CDCl₃): δ 8.14 (s, 1H), 7.96 (s,1H), 7.62 (s, 1H), 7.57-7.48 (m, 3H), 7.39 (t, J = 7.5 Hz, 1H), 7.20 (d,J = 6.9 Hz, 1H), 6.34 (s, 1H), 3.04 (s, 3H), 3.04-2.97 (m, 1H), 1.31 (d,J = 6.3 Hz, 6H). 51 N-(4-(1-(3-(pyrrolidin-1- yl)phenyl)-1H-pyrazol-4-yl)phenyl) methanesulfonamide

LC/MS: 383.1 [M + 1]^(+;) ¹H NMR (300 MHz, CDCl₃): δ 8.12 (s, 1H), 7.95(s, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.31- 7.24 (m, 3H), 6.95-6.90 (m,2H), 6.51 (dd, J = 8.4 and 2.4 Hz, 1H), 6.34 (s, 1H), 3.36 (t, J = 6.3Hz, 4H), 3.03 (s, 3H), 2.06- 2.02 (m, 4H).

Example 52:5-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)-N-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine

To a solution of5-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine (0.080 g,0.3 mmol) in dichloroethane (5 mL) was added tetrahydro-4H-pyran-4-one(0.159 mL, 1.7 mmol), acetic acid (0.033 mL, 0.6 mmol) and Sodiumtriacetoxyborohydride (0.181 g, 0.9 mmol). The reaction was stirred atroom temperature overnight. The mixture was diluted with saturatedsodium bicarbonate and dichloromethane. The organic layer was washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated. The residue was purified by silica gel chromatography(0-60% ethyl acetate/hexanes). The title compound was obtained as alight yellow solid (15 mg, 14.3%). LC/MS: [M+1]⁺, 364.3; ¹HNMR (300 MHz,CDCl3): δ 8.58 (d, J=5.7 Hz, 1H), 8.33 (s, 1H), 8.14 (s, 1H), 7.95 (s,1H), 7.61-7.56 (m, 2H), 7.45 (d, J=2.1 Hz, 1H), 6.46 (d, J=8.7 Hz, 1H),4.48 (brs, 1H), 4.05-3.93 (m, 3H), 3.57 (t, J=11.1 Hz, 2H), 2.85 (t,J=7.7 Hz, 2H), 2.10-2.06 (m, 2H), 1.87-1.80 (m, 2H), 1.60-1.50 (m, 2H),1.02 (t, J=7.4 Hz, 3H).

Example 53:N-isobutyl-5-(3-methyl-1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine

Step 1: 4-(4-bromo-3-methyl-1H-pyrazol-1-yl)-2-propylpyridine

A microwave vial was charged with 4-bromo-2-(n-propyl)pyridine (2.030 g,10.1 mmol,), 4-bromo-3-methyl-1H-pyrazole (1.776 g, 11.0 mmol,),copper(I) iodide (0.386 g, 2.0 mmol,), cesium carbonate (9.917 g, 30.4mmol,) and DMA (5 mL) and the sealed reaction mixture was heated to 140°C. for 16 hours. The reaction mixture was cooled to room temperature anddiluted with water and extracted with ethyl acetate (2×100 mL). Theorganic solvents were washed with water, brine and dried over MgSO4. Thesolvents were evaporated to dryness and the resultant residue waspurified by silica gel chromatography (0-50% ethyl acetate in hexanes).The collected fractions were dried to evaporation to give the productwhich contained approximately 20% by 1H NMR of its regioisomer,4-(4-bromo-5-methyl-1H-pyrazol-1-yl)-2-propylpyridine, as colorless oil(1.4 g, 49%). LC/MS: [M+2]⁺ 282.1; ¹H NMR (300 MHz, CDCl3): δ 8.53 (d,J=6.0 Hz, 1H), 7.97 (s, 1H), 7.44 (d, J=2.4 Hz, 1H), 7.32 (dd, J=5.7 and2.1 Hz, 1H), 2.81 (t, J=7.5 Hz, 2H), 2.34 (s, 3H), 1.85-1.74 (m, 2H),0.97 (t, J=7.2 Hz, 3H).

Step 2:5-(3-methyl-1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine

A solution of 4-(4-bromo-3-methyl-1H-pyrazol-1-yl)-2-propylpyridine(0.600 g, 2.1 mmol,),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.471 g,2.1 mmol), and 2.0 M sodium carbonate (3.212 mL, 6.4 mmol) in DMF (10mL) was stirred at room temperature for 5 minutes, andtetrakis(triphenylphosphine)palladium(0) (0.050 g, 0.04 mmol) was added.The flask was degassed and flushed with argon. This process was repeatedthree times and the reaction mixture stirred at 110° C. overnight. Aftercooling, the mixture was diluted with water and extracted with ethylacetate (3×50 mL). The combined organic layer was washed with brine,dried over MgSO4 and concentrated. The residue was purified by silicagel column (0-20% methanol/dichloromethane) to afford the desiredproduct (210 mg, 33%). LC/MS: [M+1]⁺ 294.1; ¹H NMR (300 MHz, CDCl3): δ8.55 (d, J=5.1 Hz, 1H), 8.18 (s, 1H), 7.99 (s, 1H), 7.54-7.52 (m, 2H),7.41-7.39 (m, 1H), 6.60 (d, J=9.0 Hz, 1H), 4.52 (bs, 2H), 2.83 (t, J=6.9Hz, 2H), 2.45 (s, 3H), 1.86-1.77 (m, 2H), 1.01 (t, J=6.9 Hz, 3H).

Step 3

To a solution of5-(3-methyl-1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine(0.070 g, 0.2 mmol) in dichloroethane (5 mL) was added isobutyraldehyde(26 μL, 0.3 mmol), acetic acid (20 μL, 0.4 mmol) and sodiumtriacetoxyborohydride (0.148 g, 0.7 mmol). The reaction was stirred atroom temperature for 4 hours. The mixture was diluted with saturatedsodium bicarbonate and dichloromethane. The organic layer was washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated. The residue was purified by silica gel chromatography(0-50% ethyl acetate/hexanes). The title compound was obtained as alight yellow oil (30 mg, 36.7%). LC/MS: 350.3 [M+1]⁺; ¹H NMR (300 MHz,CDCl₃): δ 8.54 (d, J=5.1 Hz, 1H), 8.18 (s, 1H), 7.98 (s, 1H), 7.52 (s,1H), 7.50 (s, 1H), 7.39 (d, J=5.4 Hz, 1H), 6.47 (d, J=9.0 Hz, 1H), 4.76(brs, 1H), 3.14 (t, J=5.9 Hz, 2H), 2.83 (t, J=7.7 Hz, 2H), 2.45 (s, 3H),1.96-1.79 (m, 3H), 1.03-0.98 (m, 9H).

Using the procedure of Example 53 and commercially available aldehydesor ketones in place of m-isobutyraldehyde for step 3 of Example 53, thefollowing examples were prepared:

Ex. Name Structure Analytical data 54 N- (cyclopropylmethyl)-5-(3-methyl-1-(2- propylpyridin-4-yl)- 1H-pyrazol-4- yl)pyridin-2-amine

LC-MS: 348.3 [M + 1]⁺; ¹H NMR (300 MHz, CDCl₃): δ 8.54 (d, J = 5.4 Hz,1H), 8.19 (s, 1H), 7.98 (s, 1H), 7.52 (s, 1H), 7.50 (s, 1H), 7.38 (d, J= 5.4 Hz, 1H), 6.47 (d, J = 8.7 Hz, 1H), 4.76 (brs, 1H), 3.18 (t, J =5.6 Hz, 2H), 2.83 (t, J = 7.7 Hz, 2H), 2.45 (s, 3H), 1.86-1.78 (m, 2H),1.17-1.09 (m, 1H), 1.01 (t, J = 7.2 Hz, 3H), 0.60-0.57 (m, 2H),0.30-0.28 (m, 2H). 55 N-cyclopentyl-5-(3- methyl-1-(2-propylpyridin-4-yl)- 1H-pyrazol-4- yl)pyridin-2-amine

LC/MS: [M + 1]⁺, 362.3; ¹HNMR (300 MHz, CDCl3), δ 8.54 (d, J = 5.7 Hz,1H), 8.18 (s, 1H), 7.98 (s, 1H), 7.52- 7.50 (m, 2H), 7.39 (d, J = 5.1Hz, 1H), 6.48 (d, J = 5.1 Hz, 1H), 4.70 (brs, 1H), 4.06-4.00 (m, 1H),2.83 (t, J = 7.7 Hz, 2H), 2.45 (s, 3H), 2.10-2.06 (m, 2H), 1.86-1.70 (m,8H), 1.01 (t, J = 7.2 Hz, 3H) 56 N-isopropyl-5-(3- methyl-1-(2-propylpyridin-4-yl)- 1H-pyrazol-4- yl)pyridin-2-amine

LC/MS: [M + 1]⁺, 362.3; ¹HNMR (300 MHz, CDCl3), δ 8.54 (d, J = 5.7 Hz,1H), 8.18 (s, 1H), 7.98 (s, 1H), 7.52- 7.50 (m, 2H), 7.39 (d, J = 5.1Hz, 1H), 6.48 (d, J = 5.1 Hz, 1H), 4.70 (brs, 1H), 4.06-4.00 (m, 1H),2.83 (t, J = 7.7 Hz, 2H), 2.45 (s, 3H), 2.10-2.06 (m, 2H), 1.86-1.70 (m,8H), 1.01 (t, J = 7.2 Hz, 3H). 57 N-cyclobutyl-5-(3- methyl-1-(2-propylpyridin-4-yl)- 1H-pyrazol-4- yl)pyridin-2-amine

LC/MS: [M + 1]⁺, 348.3; ¹HNMR (300 MHz, CDCl3), δ 8.54 (d, J = 5.7 Hz,1H), 8.17 (s, 1H), 7.97 (s, 1H), 7.52- 7.40 (m, 3H), 6.40 (d, J = 5.1Hz, 1H), 4.90 (brs, 1H), 4.19- 4.16 (m, 1H), 2.83 (t, J = 7.7 Hz, 2H),2.48-2.45 (m, 5H), 1.94-1.78 (m, 6H), 1.01 (t, J = 7.2 Hz, 3H)

Example 58:1,1,1-trifluoro-N-(5-(3-methyl-1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-yl)methanesulfonamide

Pyridine (0.046 mL, 0.6 mmol) was added dropwise to a solution oftriflic anhydride (0.097 mL, 0.6 mmol) at 0° C. under nitrogen indichloromethane (5 mL) over 10 minutes. The reaction mixture was stirredat the same temperature for 30 minutes. A solution of5-(3-methyl-1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine(0.060 g, 0.2 mmol) in dichloromethane (3 mL) was added dropwise over 20minutes. The reaction was then allowed to come to room temperature andstirred for 1 hour. Upon completion, ice water was added and thedichloromethane layer was separated. The aqueous was extracted withdichloromethane (2×50 mL). The dichloromethane extracts were combinedand dried over anhydrous sodium sulfate and concentrated under reducedpressure. The resulting residue was purified by reverse phase Prep HPLC.The title compound was obtained as a light yellow solid (15 mg, 17.2%).LC/MS: [M+1]⁺, 426.1; ¹HNMR (300 MHz, DMSO-d6): δ 8.60 (d, J=6.0 Hz,1H), 8.38 (s, 1H), 8.16 (s, 1H), 8.08-7.98 (m, 2H), 7.54 (s, 1H), 7.45(dd, J=6.0 and 1.8 Hz, 1H), 2.87 (t, J=8.0 Hz, 2H), 2.51 (s, 3H),1.88-1.80 (m, 2H), 1.02 (t, J=7.7 Hz, 3H).

Example 59:N-(3-chloro-4-(1-(6-oxo-1-propyl-1,6-dihydropyridin-3-yl)-1H-pyrazol-4-yl)phenyl)cyclopropanesulfonamide

Step 1:5-(4-(2-chloro-4-nitrophenyl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one

A microwave vial was charged with5-(4-bromo-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one (0.250 g, 0.9mmol,), (2-chloro-4-nitrophenyl)boronic acid (0.196 g, 1.0 mmol), anddioxan (8 mL) and water (2 mL) and the flask was degassed and flushedwith argon. PdCl₂(dppf) (0.073 g, 0.1 mmol,) was added and the reactionflask was again degassed and flushed with argon. The reaction mixturewas then heated to 100° C. in a microwave for 45 minutes. The reactionwas cooled to room temperature and quenched with sat. NaHCO₃ andextracted with ethyl acetate (3×50 mL). The combined organics werewashed with water, brine and dried over MgSO₄. The solvents wereevaporated to dryness and the residue purified by flash chromatography(silica gel, 0-60% ethyl acetates in hexanes) to afford the product asyellow solid (170 mg, 54%). LC/MS: [M+1]⁺, 359.1; ¹H NMR (300 MHz,CDCl₃): δ 8.37 (d, J=3.0 Hz, 1H), 8.24 (s, 1H), 8.18-8.14 (m, 1H), 8.05(s, 1H), 7.82 (d, J=3.0 Hz, 1H), 7.69-7.65 (m, 2H), 6.70 (d, J=9.3 Hz,11H), 3.98 (t, J=7.5 Hz, 2H), 1.89-1.82 (m, 2H), 1.01 (t, J=7.5 Hz, 3H).

Step 2:5-(4-(4-amino-2-chlorophenyl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one

A round bottom flask was charged with5-(4-(2-chloro-4-nitrophenyl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one(0.170 g, 0.5 mmol,), ethanol (20 mL) and Tin(II) chloride (0.328 g, 1.7mmol,) was added and the reaction mixture heated to 85° C. for 45 min.The reaction mixture was cooled and poured into 50 mL of 2M KOH. Thiswas extracted with IPA/CHCl3 (1:3, 3×50 mL). The combined organics werewashed with brine and dried over MgSO4. The solvents were evaporated togive the product as pale yellow solid which was used in the nextreaction without further purification (110 mg, 70%). LC/MS: [M+1]⁺,329.2; ¹H NMR (300 MHz, DMSO-d6): δ 8.42 (s, 1H), 8.26 (d, J=3.0 Hz,1H), 7.94 (dd, J=7.2 and 3.0 Hz, 1H), 7.90 (s, 1H), 7.25 (d, J=8.7 Hz,1H), 6.68 (d, J=2.4 Hz, 1H), 6.55 (dd, J=8.1 and 2.4 Hz, 1H), 6.51 (d,J=9.9 Hz, 1H), 5.44 (s, 2H), 3.8 (t, J=7.8 Hz, 2H), 1.73-1.63 (m, 2H),0.87 (t, J=6.9 Hz, 3H).

Step 3:N-(3-chloro-4-(1-(6-oxo-1-propyl-1,6-dihydropyridin-3-yl)-1H-pyrazol-4-yl)phenyl)cyclopropanesulfonamide

A round bottom flask was charged with5-(4-(4-amino-2-chlorophenyl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one(0.110 g, 0.3 mmol,), dichloromethane (20 mL) and flask was cooled to 0°C. and pyridine (81 μL, 1.0 mmol) followed by cyclopropanesulfonylchloride (102 μL, 1.0 mmol) were added under argon. The reaction wasstirred over night at room temperature. Another portion ofCyclopropanesulfonyl chloride (102 μL, 1.0 mmol) was added followed byaddition of DMAP (20 mg). The reaction mixture was stirred for another24 hours. The reaction mixture was quenched with water and extractedwith dichloromethane (3×25 mL). The combined organics were washed withbrine and dried over MgSO₄. The solvents were concentrated to drynessand purified by reverse phase HPLC to give the product as white solid(35 mg, 24%). LC/MS: [M+1]⁺: 433.1; ¹H NMR (300 MHz, CDCl₃): δ 8.07 (s,1H), 7.93 (s, 1H), 7.79 (d, J=3.0 Hz, 1H), 7.67 (dd, J=9.9 and 3.0 Hz,1H), 7.46 (d, J=8.1 Hz, 1H), 7.40 (d, J=2.4 Hz, 1H), 7.22 (dd, J=8.4 and2.4 Hz, 1H), 6.70 (d, J=9.9 Hz, 1H), 6.47 (bs, 1H), 3.98 (t, J=7.5 Hz,2H), 2.57-2.49 (m, 1H), 1.89-1.81 (m, 2H), 1.27-1.21 (m, 2H), 1.06-0.98(m, 5H).

Example 60:N-(3-fluoro-4-(1-(6-oxo-1-propyl-1,6-dihydropyridin-3-yl)-1H-pyrazol-4-yl)phenyl)cyclopropanesulfonamide

Step 1:5-(4-(4-amino-2-fluorophenyl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one

A microwave vial was charged with5-(4-bromo-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one (0.200 g, 0.7mmol), 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(0.168 g, 0.7 mmol), and dioxan (8 mL) and water (2 mL) and the flaskwas degassed and flushed with argon. PdCl₂(dppf) (0.058 g, 0.1 mmol) wasadded and the reaction flask was again degassed and flushed with argon.The reaction mixture was then heated to 100° C. in a microwave for 2hours. The reaction was cooled to room temperature and quenched withsat. NaHCO₃ and extracted with ethyl acetate (3×50 mL). The combinedorganics were washed with water, brine and dried over MgSO₄. Thesolvents were evaporated to dryness and the residue purified by flashchromatography (silica gel, 0-100% ethyl acetates in hexanes) to affordthe product as pale yellow oil (100 mg, 45%). LC/MS: [M+1]⁺: 313.1; ¹HNMR (300 MHz, CDCl₃): δ 7.92-7.90 (m, 2H), 7.75 (d, J=3.0 Hz, 1H), 7.66(dd, J=9.9 and 3.0 Hz, 1H), 7.32 (t, J=8.7 Hz, 1H), 6.66 (d, J+9.9 Hz,1H), 6.50-6.43 (m, 2H), 3.94 (t, J=6.9 Hz, 2H), 3.87 (bs, 2H), 1.86-1.78(m, 2H), 0.98 (t, J=7.5 Hz, 3H).

Step 2:N-(3-fluoro-4-(1-(6-oxo-1-propyl-1,6-dihydropyridin-3-yl)-1H-pyrazol-4-yl)phenyl)cyclopropanesulfonamide

A round bottom flask was charged with5-(4-(4-amino-2-fluorophenyl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one(0.100 g, 0.3 mmol), dichloromethane (20 mL) and flask was cooled to 0°C. and pyridine (74 μL, 0.9 mmol) followed by cyclopropanesulfonylchloride (93 μL, 0.9 mmol) were added under argon. The reaction wasstirred over night at room temperature. Another portion ofcyclopropanesulfonyl chloride (93 μL, 0.9 mmol) was added followed byaddition of DMAP (20 mg). The reaction mixture was stirred for another24 hours. The reaction mixture was quenched with water and extractedwith DCM (3×25 mL). The combined organics were washed with brine anddried over MgSO₄. The solvents were concentrated to dryness and theresidue purified by reverse phase HPLC to give the product as paleyellow solid (35 mg, 23%). LC/MS: [M+1]⁺: 417.1; ¹H NMR (300 MHz,CD₃OD): δ 8.43 (s, 1H), 8.21 (d, J=2.7 Hz, 1H), 8.08 (s, 1H), 8.01 (dd,J=9.3 and 3.0 Hz, 1H), 7.67 (t, J=8.4 Hz, 1H), 7.18-7.10 (m, 2H), 6.68(d, J=9.9 Hz, 1H), 4.04 (t, J=6.9 Hz, 2H), 2.64-2.56 (m, 1H), 1.87-1.77(m, 2H), 1.11-0.94 (m, 7H).

Example 61:N-(3-cyano-4-(1-(6-oxo-1-propyl-1,6-dihydropyridin-3-yl)-1H-pyrazol-4-yl)phenyl)methanesulfonamide

Step 1:1-propyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyridin-2(1H)-one

A round bottom flask was charged with5-(4-bromo-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one (0.800 g, 2.8mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(1.440 g, 5.7 mmol), Potassium Acetate (0.835 g, 8.5 mmol) and DMSO (5mL) and the flask was degassed and flushed with argon. PdCl₂(dppf)(0.116 g, 0.1 mmol) was added and the reaction flask was again degassedand flushed with argon. The reaction mixture was then heated to 70° C.overnight under argon. The reaction mixture was cooled to roomtemperature and quenched with saturated NaHCO₃ solution and extractedwith ethyl acetate (3×50 mL). The combined organics were washed withwater, brine and dried over MgSO₄. The solvents were concentrated todryness and the residue purified by flash chromatography (silica, 0-100%ethyl acetate in hexanes) to get the product as pale brown oil (600 mg,64.3%). LC/MS: [M+1]⁺:330.3; ¹H NMR (300 MHz, CDCl3): δ 7.97 (s, 1H),7.90 (s, 1H), 7.76 (d, J=3.0 Hz, 1H), 7.61 (dd, J=9.9 and 3.0 Hz, 1H),6.64 (d, J=9.9 Hz, 1H), 3.93 (t, J=7.8 Hz, 2H), 1.87-1.76 (m, 2H), 1.32(s, 12H), 0.96 (t, J=7.8 Hz, 3H).

Step 2:5-nitro-2-(1-(6-oxo-1-propyl-1,6-dihydropyridin-3-yl)-1H-pyrazol-4-yl)benzonitrile

A microwave vial was charged with1-propyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyridin-2(1H)-one(0.200 g, 0.6 mmol), 2-bromo-5-nitrobenzonitrile (0.180 g, 0.8 mmol),and dioxan (8 mL) and water (2 mL) and the flask was degassed andflushed with argon. PdCl₂(dppf) (0.058 g, 0.1 mmol) was added and thereaction flask was again degassed and flushed with argon. The reactionmixture was then heated to 100° C. in a microwave for 45 minutes. Thereaction was cooled to room temperature and quenched with sat. NaHCO₃and extracted with ethyl acetate (3×50 mL). The combined organics werewashed with water, brine and dried over MgSO₄. The solvents wereevaporated to dryness and the residue purified by flash chromatography(silica gel, 0-60% ethyl acetates in hexanes) to afford the product asyellow solid (170 mg, 80%). LC/MS: [M+1]⁺, 350.2; ¹H NMR (300 MHz,CDCl₃): δ 8.60 (d, J=2.4 Hz, 1H), 8.47 (t, J=2.4 Hz, 1H), 8.44 (d, J=2.4Hz, 1H), 8.15 (s, 1H), 7.84-7.82 (m, 2H), 7.70-7.65 (m, 1H), 6.71 (d,J=9.9 Hz, 1H), 3.98 (t, J=7.5 Hz, 2H), 1.89-1.81 (m, 2H), 1.02 (t, J=6.9Hz, 3H).

Step 3:5-amino-2-(1-(6-oxo-1-propyl-1,6-dihydropyridin-3-yl)-1H-pyrazol-4-yl)benzonitrile

A round bottom flask was charged with5-nitro-2-(1-(6-oxo-1-propyl-1,6-dihydropyridin-3-yl)-1H-pyrazol-4-yl)benzonitrile(0.170 g, 0.5 mmol), ethanol (20 mL) and Tin(II) chloride (0.328 g, 1.7mmol) was added and the reaction mixture heated to 85° C. for 45 min.The reaction mixture was cooled and poured into 50 mL of 2M KOH. Thiswas extracted with IPA/CHCl₃ (1:3, 3×50 mL). The combined organics werewashed with brine and dried over MgSO₄. The solvents were evaporated togive the product as pale yellow solid which was used in the nextreaction without further purification (120 mg, 77%). LC/MS: [M+1]⁺,320.2; ¹H NMR (300 MHz, CDCl₃): δ 8.19 (s, 1H), 8.12 (s, 1H), 7.76 (d,J=3.0 Hz, 1H), 7.69-7.65 (m, 1H), 7.38 (d, J=8.1 Hz, 1H), 6.98 (d, J=2.4Hz, 1H), 6.91 (dd, J=8.7 and 3.0 Hz, 1H), 6.68 (d, J=9.6 Hz, 1H),3.99-3.91 (m, 4H), 1.89-1.80 (m, 2H), 1.00 (t, J=7.5 Hz, 3H).

Step 4:N-(3-cyano-4-(1-(6-oxo-1-propyl-1,6-dihydropyridin-3-yl)-1H-pyrazol-4-yl)phenyl)methanesulfonamide

A round bottom flask was charged with5-amino-2-(1-(6-oxo-1-propyl-1,6-dihydropyridin-3-yl)-1H-pyrazol-4-yl)benzonitrile(0.120 g, 0.4 mmol), dichloromethane (20 mL) and flask was cooled to 0°C. and pyridine (89 μL, 1.1 mmol) followed by Methanesulfonyl chloride(112 μL, 1.3 mmol) were added under argon. The reaction was stirred for2 hours at room temperature. The reaction mixture was quenched withwater and extracted with dichloromethane (3×25 mL). Product precipitatedout from the organic extract which was collected by filtration and driedunder vacuum over night to give the product as tan colored solid (53 mg,35%). LC/MS: [M+1]⁺: 398.2; ¹H NMR (300 MHz, DMSO-d6): δ 10.21 (s, 1H),8.69 (s, 1H0, 8.30 (d, J=2.4 Hz, 1H), 8.15 (s, 1H), 7.93 (dd, J=9.6 and3.0 Hz, 1H, 7.73 (d, J=8.7 HZ, 1H), 7.58 (d, J=1.8 Hz, 1H), 7.51 (dd,J=8.7 and 2.4 Hz, 1H), 6.55 (d, J=9.6 Hz, 1H), 3.90 (t, J=6.9 Hz, 2H),3.11 (s, 3H), 1.73-1.65 (m, 2H), 0.88 (t, J=7.5 Hz, 3H).

Example 62:N-(4-(1-(6-oxo-1-propyl-1,6-dihydropyridin-3-yl)-1H-pyrazol-4-yl)-3-(trifluoromethyl)phenyl)methanesulfonamide

Step 1:5-(4-(4-nitro-2-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one

A micro wave vial was charged with1-propyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyridin-2(1H)-one(0.200 g, 0.6 mmol), 2-bromo-5-nitrobenzotrifluoride (0.180 g, 0.8mmol), and dioxan (8 mL) and water (2 mL) and the flask was degassed andflushed with argon. PdCl₂(dppf) (0.050 g, 0.1 mmol) was added and thereaction flask was again degassed and flushed with argon. The reactionmixture was then heated to 100° C. in a microwave for 45 minutes. Thereaction was cooled to room temperature and quenched with sat. NaHCO₃and extracted with ethyl acetate (3×50 mL). The combined organics werewashed with water, brine and dried over MgSO₄. The solvents wereevaporated to dryness and the residue purified by flash chromatography(silica gel, 0-60% ethyl acetates in hexanes) to afford the product asyellow solid (170 mg, 71%). LC/MS: [M+1]⁺, 393.3; ¹H NMR (300 MHz,CDCl₃): δ 8.66 (d, J=2.4 Hz, 1H), 8.43 (dd, J=9.0 and 2.4 Hz, 1H), 7.91(s, 1H), 7.85 (s, 1H), 7.81 (d, J=3.0 Hz, 1H), 7.70-7.62 (m, 2H), 6.70(d, J=9.3 Hz, 1H), 3.98 (t, J=7.5 Hz, 2H), 1.90-1.81 (m, 2H), 1.02 (t,J=6.9 Hz, 3H).

Step 2:5-(4-(4-amino-2-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one

A round bottom flask was charged with5-(4-(4-nitro-2-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one(0.170 g, 0.4 mmol), ethanol (20 mL) and Tin(II) chloride (0.328 g, 1.7mmol) was added and the reaction mixture heated to 85° C. for 45 min.The reaction mixture was cooled and poured into 50 mL of 2M KOH. Thiswas extracted with IPA/CHCl3 (1:3, 3×50 mL). The combined organics werewashed with brine and dried over MgSO₄. The solvents were evaporated togive the product as pale yellow solid which was used in the nextreaction without further purification (120 mg, 76%). LC/MS: [M+1]⁺,363.3; ¹H NMR (300 MHz, CDCl₃): δ 7.77 (d, J=3.0 Hz, 1H), 7.70 (d, J=4.5Hz, 2H), 7.64 (dd, J=9.3 and 3.0 Hz, 1H), 7.20 (d, J=8.1 Hz, 1H), 7.04(d, J=2.4 Hz, 1H), 6.83 (dd, J=8.4 and 2.4 Hz, 1H), 6.67 (d, J=10.2 Hz,1H), 3.96 (t, J=7.8 Hz, 2H), 3.92 (bs, 2H), 1.88-1.80 (m, 2H), 1.0 (t,J=7.5 Hz, 3H).

Step 3:N-(4-(1-(6-oxo-1-propyl-1,6-dihydropyridin-3-yl)-1H-pyrazol-4-yl)-3-(trifluoromethyl)phenyl)methanesulfonamide

A round bottom flask was charged with5-(4-(4-amino-2-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one(0.120 g, 0.3 mmol), DCM (20 mL) and flask was cooled to 0° C. andpyridine (89 μL, 1.1 mmol), followed by Methanesulfonyl chloride (112μL, 1.3 mmol) were added under argon. The reaction was stirred for 2hours at room temperature. The reaction mixture was quenched with waterand extracted with dichloromethane (3×25 mL). Precipitate from theorganic extract was collected by filtration and dried to give theproduct as a yellow solid (43 mg, 29%). LC/MS: [M+1]⁺: 441.2; ¹H NMR(300 MHz, DMSO-d6): δ 10.21 (s, 1H), 8.39 (s, 1H), 8.29 (d, J=2.7 Hz,1H), 7.94 (dd, J=9.9 and 3.0 Hz, 1H), 7.77 (s, 1H), 7.61 (d, J=1.8 Hz,1H), 7.57-7.49 (m, 2H), 6.53 (d, J=9.9 Hz, 1H), 3.89 (t, J=7.2 Hz, 2H),3.08 (s, 3H), 1.72-1.64 (m, 2H), 0.872 (t, J=6.9 Hz, 3H).

Example 63:N-(3-chloro-4-(1-(6-oxo-1-propyl-1,6-dihydropyridin-3-yl)-1H-pyrazol-4-yl)phenyl)ethanesulfonamide

Step 1:5-(4-(2-chloro-4-nitrophenyl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one

A micro wave vial was charged with5-(4-bromo-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one (0.400 g, 1.4mmol), (2-chloro-4-nitrophenyl)boronic acid (0.29 g, 1.4 mmol),potassium carbonate (0.59 g, 4.3 mmol) and dioxan (12 mL) and water (3mL) and the flask was degassed and flushed with argon. PdCl₂(dppf)(0.116 g, 0.1 mmol) was added and the reaction flask was again degassedand flushed with argon. The reaction mixture was then heated to 100° C.in a microwave for 45 minutes. The reaction was cooled to roomtemperature and quenched with sat. NaHCO₃ and extracted with ethylacetate (3×50 mL). The combined organics were washed with water, brineand dried over MgSO₄. The solvents were evaporated to dryness and theresidue purified by flash chromatography (12 g silica gel, 0-60% ethylacetates in hexanes) to afford the product as yellow solid (160 mg,32%). ¹H NMR (300 MHz, CDCl₃): δ 8.39 (d, J=2.7 Hz, 1H), 8.25 (s, 1H),8.17 (dd, J=9.9 and 3.0 Hz, 1H), 8.07 (s, 1H), 7.83 (d, J=3.6 Hz, 1H),7.72-7.66 (m, 2H), 6.72 (d, J=9.6 Hz, 1H), 3.99 (t, J=7.8 Hz, 2H),1.91-1.83 (m, 2H), 1.03 (t, J=7.5 Hz, 3H).

Step 2:5-(4-(4-amino-2-chlorophenyl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one

A round bottom flask was charged with5-(4-(2-chloro-4-nitrophenyl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one(0.160 g, 0.4 mmol), ethanol (20 mL) and tin(II) chloride (0.423 g, 2.2mmol) was added and the reaction mixture heated to 85° C. for 45 min.The reaction mixture was cooled and poured into 20 mL of 2 M KOH. Thiswas extracted with isopropanol/chloroform (1:3, 3×50 mL). The combinedorganics were washed with brine and dried over MgSO₄. The solvents wereevaporated to give the product as pale yellow solid which was used inthe next reaction without further purification. LC/MS: [M+1]⁺ 329.2; ¹HNMR (300 MHz, CDCl₃): δ 7.98 (s, 1H), 7.87 (s, 1H), 7.78 (d, J=3.0 Hz,1H), 7.67 (dd, J=7.2 and 3.0 Hz, 1H), 7.25 (s, 1H), 6.80 (d, J=2.4 Hz,1H), 6.69-6.61 (m, 2H), 3.97 (t, J=7.8 Hz, 2H), 3.80 (bs, 2H), 1.87-1.81(m, 2H), 1.00 (t, J=6.9 Hz, 3H).

Step 3:N-(3-chloro-4-(1-(6-oxo-1-propyl-1,6-dihydropyridin-3-yl)-1H-pyrazol-4-yl)phenyl)ethanesulfonamide

A round bottom flask was charged with5-(4-(4-amino-2-chlorophenyl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one(0.09 g, 0.2 mmol), dichloromethane (15 mL) and flask was cooled to 0°C. and pyridine (60 μL, 0.7 mmol,) followed by ethanesulfonyl chloride(125 μL, 1.2 mmol,) were added under argon. The reaction was stirred atroom temperature overnight. The reaction mixture was quenched with waterand extracted with dichloromethane (3×25 mL). The solvents were removedunder reduced pressure. The solid precipitated was collected byfiltration and dried in a vacuum oven over night to give the product astan colored solid (67 mg, 65%). LC/MS: [M+1]⁺: 421.3; ¹H NMR (300 MHz,DMSO-d₆): δ 10.09 (s, 1H), 8.61 (s, 1H), 8.31 (d, J=3.0 Hz, 1H), 8.06(s, 1H), 7.97 (dd, J=9.9 and 2.7 Hz, 1H), 7.62 (d, J=8.7 Hz, 1H), 7.36(s, 1H), 7.23 (d, J=8.7 Hz, 1H), 6.54 (d, J=9.9 Hz, 1H), 3.91 (t, J=6.9Hz, 2H), 3.17 (q, J=7.4 Hz, 2H), 1.72-1.69 (m, 2H), 1.20 (t, J=6.9 Hz,3H), 0.90 (t, J=7.5 Hz, 3H).

Using the general procedure of Example 63 the following examples wereprepared.

Example ¹H NMR (DMSO-d₆, LC/MS No. Structure 300 MHz) [M + 1] 64

δ 10.04 (s, 1H), 8.62 (s, 1H), 8.31 (d, J = 2.4 Hz, 1H), 8.07 (s, 1H),7.97 (dd, J = 9.3 and 2.7 Hz, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.35 (s,1H), 7.23 (dd, J = 8.1 and 2.1 Hz, 1H), 6.54 (d, J = 9.3 Hz, 1H), 3.92(t, J = 6.9 Hz, 2H), 3.07 (s, 3H), 1.74- 1.67 (m, 2H), 0.90 (t, J = 7.5Hz, 3H). 407.2 65

δ 8.50 (s, 1H), 8.18 (d, J = 2.4 Hz, 1H), 8.08 (s, 1H), 8.00 (dd, J =9.3 and 2.4 Hz, 1H), 7.77 (s, 1H), 7.58 (s, 2H), 6.68 (d, J = 9.9 Hz,1H), 4.04 (t, J = 6.9 Hz, 2H), 2.69-2.60 (m, 1H), 1.87-1.80 (m, 2H),1.29 (t, J = 6.9 Hz, 2H), 1.02-0.96 (m, 5H). (CD₃OD) 433.3 66

δ 10.02 (s, 1H), 8.57 (s, 1H), 8.34 (d, J = 2.7 Hz, 1H), 8.10 (s, 1H),7.96 (dd, J = 9.9 and 3.0 Hz, 1H), 7.72 (t, J = 8.7 Hz, 1H), 7.14-7.07(m, 2H), 6.53 (d, J = 9.3 Hz, 1H), 3.49 (s, 3H), 2.73-2.69 (m, 1H),0.96-0.94 (m, 4H). 389.1 67

δ 8.50 (s, 1H), 8.19 (s, 1H), 8.08 (s, 1H), 8.00 (dd, J = 9.9 and 3.0Hz, 1H), 7.77 (s, 1H), 7.59 (s, 2H), 6.68 (d, J = 9.9 Hz, 1H), 4.04 (t,J = 6.9 Hz, 2H), 3.11 (q, J = 7.8 Hz, 2H), 1.86-1.81 (m, 2H), 1.37 (t, J= 7.4 Hz, 3H), 1.00 (t, J = 7.2 Hz, 3H). (CD₃OD) 421.3 68

δ 10.08 (s, 1H), 8.65 (s, 1H), 8.38 (d, J = 3.0 Hz, 1H), 8.11 (s, 1H),8.04- 8.00 (m, 1H), 7.67 (d, J = 3.0 Hz, 1H), 7.39 (d, J = 1.5 Hz, 1H),7.29-7.25 (m, 1H), 6.60 (d, J = 9.0 Hz, 1H), 3.86 (d, J = 6.9 Hz, 2H),3.11 (s, 3H), 1.34 (s, 1H), 0.55-0.47 (m, 4H). 419.3 69

δ 8.42 (s, 1H), 8.16 (d, J = 2.7 Hz, 1H), 8.03-7.99 (m, 2H), 7.56 (d, J= 8.4 Hz, 1H), 7.42 (d, J = 1.8 Hz, 1H), 7.27 (dd, J = 8.7 and 1.8 Hz,1H), 6.69 (d, J = 9.3 Hz, 1H), 3.90 (d, J = 7.2 Hz, 2H), 2.63-2.58 (m,1H), 2.25-2.20 (m, 1H), 1.08-.97 (m, 10 H). (CD₃OD) 447.1 70

δ 8.51 (s, 1H), 8.20 (d, J = 3.0 Hz, 1H), 8.08 (s, 1H), 8.00 (dd, J =9.9 and 3.0 Hz, 1H), 7.79 (d, J = 1.5 Hz, 1H), 7.62-7.55 (m, 2H), 6.68(d, J = 9.3 Hz, 1H), 4.04 (t, J = 6.9 Hz, 2H), 3.01 (s, 3H), 1.88-1.80(m, 2H), 1.00 (t, J = 7.5 Hz, 3H). (CD₃OD). 407.1 71

δ 8.48 (s, 1H), 8.19 (d, J = 3.0, 1H), 8.07 (s, 1H), 8.00 (dd, J = 9.9and 3.0 Hz, 1H), 7.55-7.43 (m, 3H), 6.68 (d, J = 9.3 Hz, 1H), 4.04 (t, J= 6.9 Hz, 2H), 3.12 (q, J = 7.8 Hz, 2H), 1.87-1.80 (m, 2H), 1.36 (t, J =7.2 Hz, 3H), 1.0 (t, J = 7.5 Hz, 3H). (CD₃OD) 405.2 72

δ 8.48 (s, 1H), 8.19 (d, J = 3.0, 1H), 8.07 (s, 1H), 8.00 (dd, J = 9.9and 3.0 Hz, 1H), 7.55-7.43 (m, 3H), 6.68 (d, J = 9.3 Hz, 1H), 4.04 (t, J= 6.9 Hz, 2H), 3.00 (s, 3H), 1.87- 1.80 (m, 2H), 1.0 (t, J = 7.5 Hz,3H). (CD₃OD) 391.2 73

δ 8.42 (s, 1H), 8.16 (d, J = 2.7 Hz, 1H), 8.08 (s, 1H), 8.02 (dd, J =10.2 and 3.0 Hz, 1H), 7.68 (t, J = 8.1 Hz, 1H), 7.13 (dt, J = 12.9 and1.8 Hz, 2H), 6.68 (d, J = 9.9 Hz, 1H), 3.90 (d, J = 7.8 Hz, 431.1 2H),2.65-2.57 (m, 1H), 2.27-2.16 (m, 1H), 1.08- 1.05 (m, 2H), 1.02-0.97 (m,8H). (CD₃OD). 74

δ 8.55 (s, 1H), 8.30 (d, J = 3.0 Hz, 1H), 8.06 (s, 1H), 7.97 (dd, J =9.9 and 2.7 Hz, 1H), 7.64- 7.59 (m, 1H), 7.00-6.91 (m, 2H), 6.54 (d, J =10.2 Hz, 1H), 3.91 (t, J = 6.9 Hz, 2H), 2.92 (s, 3H), 1.75-1.67 (m, 2H),0.89 (t, J = 7.5 Hz, 3H). 391.2 75

δ 8.59 (s, 1H), 8.31 (d, J = 2.4 Hz, 1H), 8.10 (s, 1H), 7.97 (dd, J =9.3 and 2.1 Hz, 1H), 7.74- 7.68 (m, 1H), 7.11-7.04 (m, 2H), 6.54 (d, J =9.9 Hz, 1H), 3.91 (t, J = 6.9 Hz, 2H), 3.16- 3.11 (m, 2H), 1.74-1.67 (m,2H), 1.20 (t, J = 6.9 Hz, 3H), 0.89 (t, J = 7.5 Hz, 3H). 405.2

Example 76:N-(3-chloro-4-(1-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrazol-4-yl)phenyl)cyclopropanesulfonamide

Step 1: 5-bromo-1-ethylpyridin-2(1H)-one

A round bottom flask was charged with 2-Hydroxy-5-bromopyridine (3.00 g,17.2 mmol), iodoethane (6.93 mL, 86.2 mmol), potassium carbonate (11.92g, 86.2 mmol) in acetonitrile (30 mL) under argon. The reaction mixturewas stirred at room temperature overnight. The solvents were removedunder vacuum and the residue was taken in water and extracted with ethylacetate. The combined organics were washed with brine and dried oversodium sulfate. The solvents were removed and the residue was purifiedby flash chromatography (40 g silica, 0-100% ethyl acetate in hexanes)to give a beige solid (1.8 g). LC/MS: [M+] and [M+2] 202.2, 204.1; ¹HNMR (300 MHz, CDCl₃): δ 7.40 (d, J=2.4 Hz, 1H), 7.35-7.31 (m, 1H), 6.48(d, J=9.9 Hz, 1H), 3.99-3.91 (m, 2H), 1.35 (t, J=7.4 Hz, 3H).

Step 2: 5-(4-bromo-1H-pyrazol-1-yl)-1-ethylpyridin-2(1H)-one

To a stirred solution of 5-bromo-1-ethylpyridin-2(1H)-one (1.08 g, 5.3mmol.), 4-Bromopyrazole (0.78 g, 5.3 mmol) and cesium carbonate (5.22 g,16.0 mmol.) in anhydrous dimethyl acetamide (16 mL) under argon wasadded copper(I) iodide (0.10 g, 0.5 mmol). The mixture was stirred at135° C. for 2 hours. After cooling the mixture was partitioned betweenethyl acetate and water. The organic layer was washed with brine anddried over sodium sulfate. The solvents were removed. The residue waspurified by flash chromatography (40 g silica, 0-80% ethyl acetate inhexanes) to give a light yellow solid (340 mg, 24%). LC/MS: [M+], [M+2]268.3, 270.0; ¹H NMR (300 MHz, CDCl₃): δ 7.71 (d, J=4.2 Hz, 2H),7.54-7.48 (m, 2H), 6.50 (d, J=9.3 Hz, 1H), 3.95-3.88 (m, 2H), 1.27 (t,J=7.4, 3H).

Step 3:1-ethyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyridin-2(1H)-one

A round bottom flask was charged with5-(4-bromo-1H-pyrazol-1-yl)-1-ethylpyridin-2(1H)-one (0.34 g, 1.3 mmol),bis(pinacolato)diboron (0.64 g, 2.5 mmol), potassium acetate (0.37 g,3.8 mmol) in DMSO (4.5 mL) and the flask was degassed and flushed withargon. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)complex with dichloromethane (0.05 g, 0.1 mmol.) was added and thereaction flask was again degassed and flushed with argon. The reactionmixture was then heated to 70° C. over night under argon. The reactionmixture was cooled to room temperature and quenched with saturatedNaHCO₃ solution and extracted with ethyl acetate. The combined organicswere washed with water, brine and dried over sodium sulfate. Thesolvents were concentrated and the residue purified by flashchromatography (24 g, 0-100% ethyl acetates in hexanes) to give theproduct as a light yellow solid (130 mg, 32.5%). LC/MS: [M+], [M+2]316.1, 318.2; ¹H NMR (300 MHz, CDCl₃): δ 7.92 (s, 1H), 7.80 (s, 1H),7.74 (s, 1H), 7.56 (d, J=9.6 Hz, 1H), 6.54 (d, J=9.3 Hz, 1H), 3.98-3.90(m, 2H), 1.31-1.14 (m, 15H).

Step 4:N-(3-chloro-4-(1-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrazol-4-yl)phenyl)cyclopropanesulfonamide

A micro wave vial was charged with1-ethyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyridin-2(1H)-one(0.12 g, 0.4 mmol), N-(4-bromo-3-chlorophenyl)cyclopropanesulfonamide(0.12 g, 0.4 mmol.), potassium carbonate (0.16 g, 1.2 mmol) in dioxane(4 mL) and water (0.5 mL) and the flask was degassed and flushed withargon. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)complex with dichloromethane (0.03 g, 0.01 mmol) was added and thereaction flask was degassed and flushed with argon again. The reactionmixture was heated to 100° C. in the microwave for 45 minutes. Thereaction was cooled to room temperature and quenched with water andextracted with ethyl acetate. The organics were washed with water, brineand dried over sodium sulfate. The solvents were evaporated and theresidue was purified by flash chromatography (24 g silica, 0-10%methanol in dichloromethane) to afford the product as a light brownsolid (42.5 mg, 26%). LC/MS: [M+1] 419.4; ¹H NMR (300 MHz, CD₃OD): δ8.42 (s, 1H), 8.21 (d, J=3.0 Hz, 1H), 8.02 (d, J=4.2 Hz, 1H), 7.98 (d,J=3.0 Hz, 1H), 7.56 (d, J=8.7 Hz, 1H), 7.42 (d, J=1.8 Hz, 1H), 7.29-7.25(m, 1H), 6.68 (d, J=10.2 Hz, 1H), 4.15-4.08 (m, 2H), 2.63-2.58 (m, 1H),1.40 (t, J=7.4 Hz, 3H), 1.07 (d, J=4.8 Hz, 2H), 1.00 (d, J=8.1 Hz, 2H).

Using the general procedure of Example 76 the following examples wereprepared.

Example ¹H NMR (DMSO-d₆, LC/MS No. Structure 300 MHz) [M + 1] 77

δ 10.07 (s, 1H), 8.65 (s, 1H), 8.38 (s, 1H), 8.11 (s, 1H), 8.02 (d, J =9.3 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.42 (s, 1H), 7.30 (d, J = 8.1Hz, 1H), 6.60 (d, J = 9.9 Hz, 1H), 3.86 (d, J = 6.9 Hz, 2H), 2.76 (s,1H), 1.34 (s, 1H), 1.01 (d, J = 5.1 Hz, 4H), 0.55-0.48 (m, 4H). 447.2[M + 2] 78

δ 7.91 (s, 1H), 7.79 (d, J = 2.7 Hz, 1H), 7.69- 7.60 (m, 2H), 7.30 (d, J= 7.2 Hz, 1H), 6.70 (d, J = 9.3 Hz, 1H), 6.47 (s, 1H), 3.98 (t, J = 6.8Hz, 2H), 2.55-2.50 (m, 1H), 1.90-182 (m, 2H), 1.23- 1.17 (m, 2H),1.04-0.97 (m, 5H). (CDCl₃) 417.4 79

δ 8.05 (d, J = 1.5 Hz, 1H), 8.00 (s, 1H), 7.75 (d, J = 2.7 Hz, 1H), 7.69(dd, J = 9.9 and 3.0 Hz, 1H), 7.55 (t, J = 8.3 Hz, 1H), 7.17 (dd, J =12.0 and 2.1 Hz, 1H), 7.05 (dd, J = 8.7 and 1.8 Hz, 1H), 431.5 6.71 (d,J = 8.7 Hz, 1H), 6.49 (s, 1H), 3.84 (d, J = 7.5 Hz, 2H), 2.57-2.52 (m,1H), 2.28-2.21 (m, 1H), 1.24-1.23 (m, 2H), 1.06-0.99 (m, 8H). 80

δ 9.56 (s, 1H), 8.77 (s, 1H), 8.02 (s, 2H), 7.96- 7.91 (m, 1H), 7.60 (d,J = 6.9 Hz, 1H), 7.48 (d, J = 8.1 Hz, 1H), 7.43 (t J = 10.2 Hz, 1H),6.56 (d, J = 9.9 Hz, 1H), 3.78 (d, J = 6.9 Hz, 2H), 2.66-2.61 (m, 1H),2.15-2.09 (m, 1H), 0.96-0.87 (m, 10H). 431.4

Example 81:N-(3-chloro-4-(1-(1-((1-methylazetidin-3-yl)methyl)-6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrazol-4-yl)phenyl)cyclopropanesulfonamide

Step 1: tert-butyl3-((5-bromo-2-oxopyridin-1(2H)-yl)methyl)azetidine-1-carboxylate

A round bottom flask was charged with 2-hydroxy-5-bromopyridine (1.0 g,5.7 mmol) and 1,2-dimethoxyethane (30 mL) and potassium tert-butoxide(0.65 g, 5.7 mmol) was added and the reaction mixture stirred at roomtemperature for 30 minutes, potassium carbonate (0.56 g, 4.0 mmol) and1-Boc-3-bromomethylazetidine (2.88 g, 11.5 mmol) were added and thereaction mixture heated to reflux overnight. The reaction mixture wascooled to room temperature and quenched with water and extracted withethyl acetate (3×100 mL). The combined organics were washed with brineand dried over MgSO₄. The solvents were evaporated to dryness and theresidue purified by flash chromatography (40 g silica, 0-100% ethylacetate in hexanes) to give the product as white solid (1.65 g, 84%).LC/MS: [M+]343.2; ¹H NMR (300 MHz, CDCl₃): δ 7.39-7.34 (m, 2H), 6.49 (d,J=9.3 Hz, 1H), 4.08-3.97 (m, 4H), 3.72-3.67 (m, 2H), 3.07-3.05 (m, 1H),1.44 (s, 9H),

Step 2: tert-butyl3-((5-(4-bromo-1H-pyrazol-1-yl)-2-oxopyridin-1(2H)-yl)methyl)azetidine-1-carboxylate

To a stirred solution of tert-butyl3-((5-bromo-2-oxopyridin-1(2H)-yl)methyl)azetidine-1-carboxylate (1.65g, 4.8 mmol), 4-bromopyrazole (1.1 g, 7.6 mmol) and cesium carbonate(7.47 g, 22.9 mmol) in anhydrous dimethyl acetamide (10 mL) under argonwas added copper(I) iodide (0.07 g, 0.4 mmol). The mixture was stirredat 130° C. for 2 hours. After cooling, the mixture was partitionedbetween ethyl acetate and water. The layers were separated and theaqueous layer was extracted twice with ethyl acetate. The combinedorganics were washed with brine and dried over MgSO₄. The solvents wereremoved and resulting residue was purified by flash chromatography(0-100% ethyl acetate in hexanes) to give the product as oil. LC/MS:[M+], [M+2]⁺ 409 and 411; ¹H NMR (300 MHz, CDCl₃): δ 7.71-7.69 (m, 2H),7.62-7.56 (m, 2H), 6.67 (d, J=9.9 Hz, 1H), 4.18 (m, 2H), 4.03 (t, J=8.7Hz, 2H), 3.74 (dt, J=6.0 and 3.6 Hz, 2H), 3.11-3.09 (m, 1H), 1.43 (s,9H).

Step 3: tert-butyl3-((5-(4-(2-chloro-4-(cyclopropanesulfonamido)phenyl)-1H-pyrazol-1-yl)-2-oxopyridin-1(2H)-yl)methyl)azetidine-1-carboxylate

A round bottom flask was charged with tert-butyl3-((5-(4-bromo-1H-pyrazol-1-yl)-2-oxopyridin-1(2H)-yl)methyl)azetidine-1-carboxylate(0.20 g, 0.5 mmol),N-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanesulfonamide(0.18 g, 0.5 mmol), and dioxan (4 mL) and water (1 mL) and the flask wasdegassed and flushed with argon. PdCl₂(dppf) (0.04 g, 0.05 mmol) wasadded and the reaction flask was again degassed and flushed with argon.The reaction mixture was then heated to 100° C. for 1 hour in amicrowave. The reaction mixture was cooled to room temperature andquenched with water and extracted with isopropanol/dichloromethane (1:3,3×30 mL). The combined organics were washed with brine and dried overMgSO₄. The solvents were evaporated to dryness and the residue waspurified by flash chromatography (12 g silica, 0-10% methanol indichloromethane). The fractions were evaporated to give the product aspale brown oil (150 mg, 55%). LC/MS: [M+1]⁺ 560.1; ¹H NMR (300 MHz,CDCl₃): δ 8.07 (s, 1H), 7.94 (s, 1H), 7.83 (d, J=2.7 Hz, 1H), 7.72 (dd,J=10.2 and 3.0 Hz, 1H), 7.56-7.41 (m, 2H), 7.25-7.23 (m, 1H), 7.03 (bs,1H), 6.71 (d, J=9.3 Hz, 1H), 4.21 (bs, 2H), 4.05 (t, J=8.1 Hz, 2H),3.8-3.75 (m, 2H), 3.18-3.09 (m, 1H), 2.59-2.50 (m, 11H), 1.41 (s, 9H),1.26-1.20 (m, 2H), 1.05-0.99 (m, 2H).

Step 4:N-(4-(1-(1-(azetidin-3-ylmethyl)-6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrazol-4-yl)-3-chlorophenyl)cyclopropanesulfonamide

A round bottom flask was charged with tert-butyl3-((5-(4-(2-chloro-4-(cyclopropanesulfonamido)phenyl)-1H-pyrazol-1-yl)-2-oxopyridin-1(2H)-yl)methyl)azetidine-1-carboxylate(0.15 g, 0.3 mmol), dichloromethane (15 mL) and trifluoro acetic acid(0.06 mL, 0.8 mmol,) was added and the reaction stirred for at roomtemperature for 3 hours. The solvents were removed and the compound usedin the next step without further purification. LC/MS: [M+1]⁺ 460.7

Step 5:N-(3-chloro-4-(1-(1-((1-methylazetidin-3-yl)methyl)-6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrazol-4-yl)phenyl)cyclopropanesulfonamide

A microwave vial was charged withN-(4-(1-(1-(azetidin-3-ylmethyl)-6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrazol-4-yl)-3-chlorophenyl)cyclopropanesulfonamide(0.10 g, 0.2 mmol), iodomethane (0.06 mL, 0.9 mmol),N,N-diisopropylethylamine (0.05 mL, 0.2 mmol), DMSO (2 mL) and heated to90° C. for 3 hours. The reaction mixture was cooled to room temperatureand quenched with water and extracted with isopropanol:chloroform (1:3,3×50 mL). The combined solvents were washed water, brine and dried overMgSO₄. The solvents were evaporated to dryness and the residue purifiedby flash chromatography (4 g, 0-20% methanol in dichloromethane) to givethe product as an oil. LC/MS: [M+1]⁺ 474.5: ¹H NMR (300 MHz, CD₃OD): δ8.62 (s, 1H), 8.45 (d, J=2.4 Hz, 1H), 8.34 (dd, J=9.3 and 2.4 Hz, 1H),8.14 (s, 1H), 7.66-7.63 (m, 2H), 7.48 (dd, J=8.4 and 2.4 Hz, 1H), 7.11(d, J=9.9 Hz, 1H), 4.53-4.48 (m, 1H), 4.30-4.23 (m, 1H), 3.76-3.64 (m,3H), 3.47-3.37 (m, 4H), 2.66-2.47 (m, 2H), 1.01-0.96 (m, 4H).

Example 82:5-(4-(2-(cyclopentylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one

Step 1:5-(4-(2-(cyclopentylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one

A micro wave vial was charged with1-propyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyridin-2(1H)-one(0.15 g, 0.5 mmol), 5-bromo-N-cyclopentylpyrimidin-2-amine (0.12 g, 0.5mmol), potassium carbonate (0.19 g, 1.4 mmol) and dioxan (8 mL) andwater (2 mL) and the flask was degassed and flushed with argon.PdCl₂(dppf) (0.04 g, 0.05 mmol) was added and the reaction flask wasagain degassed and flushed with argon. The reaction mixture was thenheated to 100° C. in a microwave for 1 hour. The reaction was cooled toroom temperature and quenched with sat. NaHCO₃ and extracted with ethylacetate (3×50 mL). The combined organics were washed with water, brineand dried over MgSO₄. The solvents were evaporated to dryness and theresidue purified by flash chromatography (12 g silica gel, 0-100% ethylacetate in hexanes) to afford the product as yellow solid (52 mg, 27%).LC/MS: [M+1]⁺ 365.3; ¹HNMR (300 MHz, CDCl₃): δ 8.44 (s, 2H), 7.82 (d,J=4.8 Hz, 2H), 7.77 (d, J=3.0 Hz, 1H), 7.66 (dd, J=9.6 and 2.7 Hz, 1H),6.69 (d, J=9.9 Hz, 1H), 5.15 (d, J=7.5 Hz, 1H), 4.30-4.28 (m 1H), 3.98(t, J=7.2 Hz, 2H), 2.10-2.06 (m, 2H), 1.89-1.82 (m, 2H), 1.79-1.67 (m,4H), 1.54-1.48 (m, 2H), 1.02 (t, J=7.4 Hz, 3H).

Example 83:5-(4-(2-(tert-butylamino)pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one

The title compound was prepared analogously to Example 82.

LC/MS: [M+1]+ 353.2; ¹HNMR (300 MHz, CDCl₃): δ 8.42 (s, 2H), 7.82 (d,J=6.0 Hz, 2H), 7.77 (s, 1H), 7.66 (dd, J=9.6 and 2.1 Hz, 1H), 6.69 (d,J=9.9 Hz, 1H), 5.21 (bs, 1H), 3.98 (t, J=7.2 Hz, 2H), 1.89-1.82 (m, 2H),1.48 (s, 9H), 1.02 (t, J=7.4 Hz, 3H).

Example 84:5-(4-(6-(tert-butylamino)pyridin-3-yl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one

Step 1: 5-bromo-N-(tert-butyl)pyridin-2-amine

A microwave vial was charged with 5-bromo-2-fluoropyridine (1.0 g, 5.7mmol) and anhydrous dimethyl acetamide (10 mL) and tert-butylamine (3.00mL, 28.7 mmol.) was added and the reaction mixture heated at 140° C. for64 h. The reaction mixture was cooled to room temperature and quenchedwith water (200 mL) and extracted with ethyl acetate (3×100 mL). Thecombined organics were washed with brine and dried over MgSO₄. Thesolvents were evaporated to dryness and the residue purified by flashchromatography (40 g silica gel, 0-30% ethyl acetate in hexanes) to givethe product as colorless liquid (400 mg, 30%). LC/MS: [M+] 229.0; ¹H NMR(300 MHz, CDCl₃): δ 8.08 (d, J=2.1 Hz, 1H), 7.40 (dd, J=8.7 and 3.0 Hz,1H), 6.32 (d, J=8.1 Hz, 1H), 4.47 (bs, 1H), 1.40 (s, 9H).

Step 2:5-(4-(6-(tert-butylamino)pyridin-3-yl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one

The title compound was prepared in a manner similar to that given forExample 82. LC/MS: [M+1]⁺ 352.2; ¹H NMR (300 MHz, CD₃OD): δ 8.28 (s,1H), 8.23 (d, J=1.8 Hz, 1H), 8.13 (d, J=3.0 Hz, 1H), 7.96 (dd, J=9.3 and3.0 Hz, 1H), 7.92 (s, 1H), 7.59 (dd, J=9.0 and 3.0 Hz, 1H), 6.65 (d,J=9.3 Hz, 1H), 6.57 (d, J=8.7 Hz, 1H), 4.00 9t. J=7.5 Hz, 2H), 1.85-1.77(m, 2H), 1.43 (s, 9H), 0.98 (t, J=7.5 Hz, 3H).

Example 85:5-(4-(6-(cyclobutylamino)-4-methylpyridin-3-yl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one

Step 1:5-(4-(6-amino-4-methylpyridin-3-yl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one

A micro wave vial was charged with1-propyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyridin-2(1H)-one(0.20 g, 0.6 mmol), 2-amino-5-bromo-4-methylpyridine (0.18 g, 0.8 mmol),and dioxan (8 mL) and water (2 mL) and the flask was degassed andflushed with argon. PdCl₂(dppf) (0.05 g, 0.05 mmol) was added and thereaction flask was again degassed and flushed with argon. The reactionmixture was then heated to 100° C. in a microwave for 45 minutes. Thereaction was cooled to room temperature and quenched with sat. NaHCO₃and extracted with ethyl acetate (3×50 mL). The combined organics werewashed with water, brine and dried over MgSO₄. The solvents wereevaporated to dryness and the residue purified by flash chromatography(12 g silica gel, 0-10% methanol in dichloromethane) to afford theproduct as yellow solid (160 mg, 80%). LC/MS: [M+1]⁺ 310.1; ¹H NMR (300MHz, CDCl₃): δ 8.00 (s, 1H), 7.78 (d, J=3.0 Hz, 1H), 7.71-7.64 (m, 2H),6.68 (d, J=9.9 Hz, 1H), 6.43 (s, 1H), 4.42 (bs, 2H), 3.96 (t, J=7.8 Hz,2H), 2.29 (s, 3H), 1.89-1.78 (m, 2H), 1.0 (t, J=7.5 Hz, 3H).

Step 2:5-(4-(6-(cyclobutylamino)-4-methylpyridin-3-yl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one

A vial was charged with5-(4-(6-amino-4-methylpyridin-3-yl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one(0.07 g, 0.2 mmol), cyclobutanone (0.07 mL, 0.9 mmol) and1,2-dichloroethane (5 mL) and the reaction mixture was stirred for 15minutes and sodium triacetoxyborohydride (0.12 g, 0.6 mmol) was addedand the reaction mixture stirred at room temperature for 48 hours. Thereaction mixture was quenched with water and extracted withdichloromethane (3×25 mL). The combined organics were washed with brineand dried over MgSO₄. The solvents were evaporated to dryness and theresidue purified by reverse phase HPLC (neutral) to give the product aswhite solid (10 mg, 12%). LC/MS: [M+1]⁺ 364.2; ¹H NMR (300 MHz, CD₃OD):δ 8.17 (d, J=3.0 Hz, 1H), 8.13 (s, 1H), 8.00 (dd, J=9.9 and 3.0 Hz, 1H),7.89 (s, 1H), 7.78 (s, 1H), 6.67 (d, J=10.2 Hz, 1H), 6.40 (s, 1H),4.25-419 (m, 1H), 4.03 (t, J=7.5 Hz, 2H), 2.42-2.37 (i, 2H), 2.31 (s,3H), 1.95-1.74 (m, 6H), 1.00 (t, J=7.5 Hz, 3H).

The following compounds are made in a manner similar to that describedfor Example 85.

Example ¹H NMR (CDCl₃, LC/MS No. Structure 300 MHz) [M + 1] 86

δ 8.17 (d, J = 3.0 Hz, 1H), 8.13 (s, 1H), 8.00 (dd, J = 9.9 and 3.0 Hz,1H), 7.89 (s, 1H), 7.78 (s, 1H), 6.67 (d, J = 10.2 Hz, 1H), 6.40 (s,1H), 4.25-4.19 (m, 1H), 4.03 (t, J = 7.5 Hz, 2H), 2.42- 2.337 (m, 2H),2.31 (s, 3H), 1.95- 1.74 (m, 6H), 1.00 (t, J = 7.5 Hz, 3H). (CD₃OD)364.2 87

δ 8.02 (s, 1H), 7.78 (d, J = 3.0 Hz, 1H), 7.72-7.65 (m, 3H), 6.69 (d, J= 9.3 Hz, 1H), 6.32 (s, 1H), 3.98 9t, J = 7.5 Hz, 2H), 2.32 (s, 3H),2.1-2.04 (m, 2H), 1.90-1.66 (m, 6H), 1.51 (m, 3H), 1.02 (t, J = 7.5 Hz,3H). 378.4 88

δ 7.77 (d, J = 2.4 Hz, 1H), 7.70- 7.63 (m, 3H), 7.40 (d, J = 8.1 Hz,1H), 6.68 (d, J = 10.2 Hz, 1H), 6.31 (d, J = 8.1 Hz, 1H), 4.75 (bs, 1H),3.99-3.90 (m, 3H), 2.45 (s, 3H), 2.06-1.48 (m, 10H), 1.00 (t, J = 7.5Hz, 3H). 378.4 89

δ 7.76 (d, J = 3.0 Hz, 1H), 7.68- 7.62 (m, 3H), 7.39 (d, J = 9.0 Hz,1H), 6.66 (d, J = 9.3 Hz, 1H), 6.30 (d, J = 8.7 Hz, 1H), 4.01-3.92 (m,4H), 3.73 (m, 1H), 3.52 (t, J = 9.9 Hz, 2H), 2.45 (s, 3H), 2.04-2.0 (m,2H), 1.86-1.76 (m, 2H), 1.61-1.48 (m, 2H), 0.98 (t, J = 7.5 Hz, 3H)394.1 90

δ 8.29 (d, J = 2.4 Hz, 1H), 7.84 (s, 1H), 7.80 (s, 1H), 7.77 (d, J = 3.0Hz, 1H), 7.66 (dd, J = 9.9 and 3.0 Hz, 1H), 7.55 (dd, J = 9.1 and 2.4Hz, 1H), 6.69 (d, J = 9.9 Hz, 1H), 6.45 (d, J = 8.7 Hz, 1H), 4.43 (brs,1H), 4.04-3.95 (m, 4H), 3.61-3.53 (m, 2H), 2.09-2.05 (m, 2H), 1.89-1.82(m, 2H), 1.55-1.50 (m, 3H), 1.01 (t, J = 7.4 Hz, 3H). 380.4 91

δ 8.21 (d, J = 2.7 Hz, 1H), 8.12 (s, 1H), 8.01-7.97 (m, 1H), 7.79 (s,1H), 7.48 (d, J = 8.4, 1H), 6.68 (d, J = 9.6 Hz, 1H), 6.34 (d, J = 9.0Hz, 1H), 4.22-4.16 (m, 1H), 3.93 (d, J = 6.9 Hz, 2H), 2.45-2.38 (m, 5H),1.97-1.87 (m, 2H), 1.83- 1.75 (m, 2H), 1.40-1.34 (m, 1H), 0.65-0.58 (m,2H), 0.52-0.48 (m, 2H). (CD₃OD) 376.4 92

δ 8.35 (d, J = 2.4 Hz, 1H), 7.84 (s, 1H), 7.78-7.76 (m, 2H), 7.67 (dd, J= 9.9, 3.0 Hz, 1H), 7.55 (dd, J = 8.7, 2.4 Hz, 1H), 6.69 (d, J = 9.3 Hz,1H), 6.52 (d, J = 8.7 Hz, 1H), 3.98 (t, J = 7.4 Hz, 2H), 3.56 (q, J =7.1 Hz, 4H), 190- 1.82 (m, 2H), 1.26-1.20 (m, 6H), 1.02 (t, J = 7.4 Hz,3H). 352.4

Example 93:5-(4-(6-(cyclopentylamino)-2-methylpyridin-3-yl)-1H-pyrazol-1-yl)-1-(cyclopropylmethyl)pyridin-2(1H)-one

Step 1: 5-bromo-N-cyclopentyl-6-methylpyridin-2-amine

A vial was charged with 5-bromo-6-methylpyridin-2-amine (2.00 g, 10.7mmol), cyclopentanone (4.03 mL, 53.5 mmol) and 1,2-dichloroethane (60mL) and the reaction mixture was stirred for 15 minutes and sodiumtriacetoxyborohydride (11.28 g, 53.5 mmol) was added and the reactionmixture stirred at room temperature overnight. The reaction mixture wasquenched with water and extracted with dichloromethane (3×25 mL). Thecombined organics were washed with brine and dried over MgSO₄. Thesolvents were evaporated to dryness and the residue purified by flashchromatography (40 g silica 0-20% ethyl acetate in hexanes) to give theproduct as light yellow oil. LC/MS: [M+1]⁺ 257.2; ¹H NMR (300 MHz,CDCl₃): δ 7.49 (d, J=8.7 Hz, 1H), 6.14 (d, J=8.7 Hz, 1H), 3.80-3.76 (m,1H), 2.43 (s, 3H), 1.99-1.48 (m, 8H).

Step 2:5-(4-(6-(cyclopentylamino)-2-methylpyridin-3-yl)-1H-pyrazol-1-yl)-1-(cyclopropylmethyl)pyridin-2(1H)-one

A micro wave vial was charged with1-(cyclopropylmethyl)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyridin-2(1H)-one(0.13 g, 0.4 mmol.), 5-bromo-N-cyclopentyl-6-methylpyridin-2-amine (0.1g, 0.4 mmol.) and potassium carbonate (0.16 g, 1.1 mmol.) in dioxane (10mL) and water (0.5 mL) and the flask was degassed and flushed withargon. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)complex with dichloromethane (0.031 g, 0.01 mmol) was added and thereaction flask was degassed and flushed with argon again. The reactionmixture was heated to 100° C. in the microwave for 90 minutes. Thereaction was cooled to room temperature and quenched with water andextracted with ethyl acetate. The organics were washed with water, brineand dried over sodium sulfate. The solvents were evaporated. The residuewas purified by flash chromatography (24 g silica, 0-10% methanol indichloromethane). The product fractions were collected and the solventwas removed by vacuum. The residue was purified again by reverse phaseHPLC (neutral, 30-95% Acetonitrile/Water) to give a yellow oil (38.1mg). LC/MS: [M+1] 390.4; ¹H NMR (300 MHz, CD₃OD): δ 8.20 (d, J=2.4 Hz,1H), 8.11 (s, 1H), 8.00-7.96 (m, 1H), 7.77 (s, 1H), 7.48 (d, J=8.1 Hz,1H), 6.67 (d, J=9.3 Hz, 1H), 6.41 (d, J=8.7 Hz, 1H), 4.03-4.01 (m, 1H),3.91 (d, J=6.9 Hz, 2H), 2.44 (s, 3H), 2.05-1.99 (m, 2H), 1.76-1.66 (m,4H), 1.64-1.48 (m, 2H), 1.35-1.33 (m, 1H), 0.59 (d, J=6.9 Hz, 2H), 0.47(d, J=3.9 Hz, 2H).

The following compounds are made in a manner similar to that describedfor Example 93.

Example ¹H NMR (DMSO-d₆, LC/MS No. Structure 300 MHz) [M + 1] 94

δ 8.27 (d, J = 2.4 Hz, 1H), 8.19 (s, 1H), 8.08-8.03 (m, 1H), 7.95 (s,1H), 7.84 (s, 1H), 6.74 (d, J = 9.9 Hz, 1H), 6.50 (s, 1H), 4.15- 4.10(m, 1H), 3.98 (d, J = 7.2 Hz, 2H), 2.36 (s, 3H), 2.11-2.03 (m, 2H),1.82-1.69 (m, 4H), 1.60- 1.52 (m, 2H), 1.43-1.34 (m, 1H), 0.69-0.63 (m,2H), 0.56-0.52 (m, 2H). (CDCl₃) 390.4 95

δ 8.02 (s, 1H), 7.74-7.65 (m, 4H), 6.69 (d, J = 9.9 Hz, 1H), 6.31 (s,1H), 4.56 (bs, 1H), 4.04-3.97 (m, 1H), 3.83 (d, J = 7.5 Hz, 2H), 2.32(s, 3H), 2.28- 2.04 (m, 3H), 1.77-1.66 (m, 4H), 1.54-1.48 (m, 2H), 1.00(d, J = 6.6 Hz, 6H). (CDCl₃) 392.5 96

δ 7.74-7.65 (m, 4H), 7.41 (d, J = 5.1 Hz, 1H), 6.69 (d, J = 9.3 Hz, 1H),6.33 (d, J = 8.1 Hz, 1H), 4.68 (bs, 1H), 3.94-3.90 (m, 1H), 3.83 (d, J =7.5 Hz, 2H), 2.47 (s, 3H), 2.28-2.02 (m, 3H), 1.77-1.48 (m, 6H), 1.00(d, J = 6.6 Hz, 6H). 392.5 97

δ 7.74-7.65 (m, 4H), 7.40 (d, J = 8.4 Hz, 1H), 6.69 (d, J = 9.3 Hz, 1H),6.22 (d, J = 8.4 Hz, 1H), 4.85 (bs, 1H), 4.12-4.04 (m, 1H), 3.83 (d, J =7.5 Hz, 2H), 2.47-2.44 (m, 4H), 2.30- 1.74 (m, 6H), 1.00 (d, J = 6.6 Hz,6H). (CD₃OD) 378.5 98

δ 8.10 (s, 2H), 8.00-7.95 (m, 1H), 7.77 (s, 1H), 7.45 (d, J = 7.2 Hz,1H), 6.66 (d, J = 9.9 Hz, 1H), 6.41 (d, J = 8.1 Hz, 1H), 4.43-4.41 (m,1H), 4.01-3.96 (m, 2H), 3.89-3.82 (m, 3H), 3.82-3.63 (m, 1H), 3.30 (s,3H), 2.45-2.19 (m, 2H), 1.93-1.83 (m, 1H), 0.97 (d, J = 7.2 Hz, 6H).(CD₃OD) 394.4 99

δ 8.12 (d, J = 3.3 Hz, 2H), 8.02-7.97 (m, 1H), 7.78 (s, 1H), 7.48 (d, J= 9.0 Hz, 1H), 6.68 (d, J = 9.6 Hz, 1H), 6.32 (d, J = 8.7 Hz, 1H),4.04-3.99 (m, 1H), 3.90 (d, J = 7.8 Hz, 2H), 2.54-2.47 (m, 2H), 2.44 (s,3H), 2.25-2.20 (m, 1H), 2.11 (t, J = 7.1 Hz, 2H), 1.98 (t, J = 7.1 Hz,1H), 1.91-1.82 (m, 5H), 0.97 (d, J = 6.3 Hz, 6H). (CD₃OD) 418.6 100

δ 8.13 (s, 2H), 8.02-7.98 (m, 1H), 7.89 (s, 1H), 7.78 (s, 1H), 6.68 (d,J = 10.2, 1H), 6.40 (s, 1H), 4.24- 4.19 (m, 1H), 3.89 (d, J = 7.2 Hz,2H), 2.43-2.39 (m, 2H), 2.31 (s, 3H), 2.25- 2.20 (m, 1H), 1.96-1.89 (m,2H), 1.82-1.77 (m, 2H), 0.98 (d, J = 6.9 Hz, 6H). (CD₃OD) 378.5 101

δ 8.16 (d, J = 2.1 Hz, 1H), 8.12 (s, 1H), 8.02-7.98 (m, 1H), 7.79 (s,1H), 7.46 (d, J = 8.7 Hz, 1H), 6.67 (d, J = 9.6 Hz, 1H), 6.43 (d, J =8.7 Hz, 1H), 4.44-4.42 (m, 1H), 4.06-3.92 (m, 4H), 3.88-3.83 (m, 1H),3.68-3.65 (m, 1H), 2.46 (s, 3H), 2.33-2.26 (m, 1H), 1.90-1.80 (m, 3H),0.99 (t, d = 7.5 Hz, 3H). (CD₃OD) 379.4 102

δ 7.82-7.77 (m, 2H), 7.69 (d, J = 10.2 Hz, 1H), 7.57- 7.51 (m, 2H), 7.22(d, J = 6.0 Hz, 1H), 6.71 (d, J = 9.9 Hz, 1H), 4.92 (bs, 2H), 4.00 (t, J= 6.9 Hz, 2H), 2.67 (s, 3H), 1.88-1.83 (m, 4H), 1.27 (bs, 2H), 1.03 (t,J = 7.5 Hz, 3H). (CDCl₃) 364.4 103

δ 7.78 (s, 1H), 7.71-7.67 (m, 3H), 7.39 (d, J = 9.0 Hz, 1H), 6.69 (d, J= 9.9 Hz, 1H), 6.19 (d, J = 8.7 Hz, 1H), 4.73 (bs, 1H), 4.00-3.96 (m,3H), 2.57- 2.50 (m, 2H), 2.46 (s, 3H), 2.09-1.85 (m, 10H), 1.02 (t, J =7.5 Hz, 3H). (CDCl₃) 404.6 104

δ 7.78 (s, 1H), 7.71-7.67 (m, 3H), 7.38 (d, J = 9.7 Hz, 1H), 6.69 (d, J= 9.9 Hz, 1H), 6.27 (d, J = 9.1 Hz, 1H), 4.62 (bs, 1H), 3.98 (t, J = 6.8Hz, 2H), 3.28-3.26 (m, 1H), 2.47 (s, 3H), 1.90-183 (m, 2H), 1.28 (d, J =6.3 Hz, 3H), 378.5 1.02 (t, J = 7.4 Hz, 3H), 0.52-0.29 (m, 4H). (CDCl₃)105

δ 7.77 (bs, 2H), 7.69 (d, J = 9.6 Hz, 1H), 7.57-7.51 (m, 2H), 7.22 (m,1H), 6.71 (d, J = 9.3 Hz, 1H), 4.92 (bs, 2H), 3.85 (d, J = 6.9 Hz, 2H),3.65 (bs, 3H), 2.67 (s, 3H), 2.29-2.23 (m, 2H), 1.01 (d, J = 6.6 Hz,6H). (CDCl₃) 378.5

Example 106:N-(cyclopropylmethyl)-2-methyl-6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-amine

Step 1: 4-(4-bromo-1H-pyrazol-1-yl)-2-propylpyridine

To a stirred solution of 4-bromo-2-(n-propyl)pyridine (4.0 g, 20.0mmol), 3-bromopyrazole (3.5 g, 24.0 mmol), potassium carbonate (5.526 g,40.0 mmol, 2.0 equiv.) in anhydrous toluene (40 mL) under argon wereadded trans-N,N-dimethyl-1,2-cyclohexanediamine (0.6 mL, 4.0 mmol) andcopper(I) iodide (0.19 g, 1.0 mmol). The mixture was stirred at 100° C.overnight. After cooling, the mixture was partitioned between ethylacetate and water. The layers were separated and the aqueous layer wasextracted twice with ethyl acetate. The combined organics were washedwith brine and dried over MgSO₄. The solvents were removed and resultingresidue purified by flash chromatography (80 g, 0-40% ethyl acetate inhexanes). The title compound was obtained as a thick oil (2.89 g,54.3%). LC/MS: [M+1]⁺ 268.1; ¹H NMR (300 MHz, CDCl₃): δ 8.59 (d, J=5.1Hz, 1H), 8.06 (s, 1H), 7.73 (s, 1H), 7.49 (d, J=1.8 Hz, 1H), 7.38 (dd,J=5.7 and 2.4 Hz, 1H), 2.84 (t, J=7.5 Hz, 2H), 1.85-1.78 (m, 2H), 1.00(t, J=7.5 Hz, 3H).

Step 2:2-propyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyridine

To a stirred solution of 4-(4-bromo-1H-pyrazol-1-yl)-2-propylpyridine(2.1 g, 7.9 mmol) in DMSO (35 mL) was added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (3.0 g, 11.8mmol) and potassium acetate (2.3 g, 23.7 mmol) followed by1,1′-bis(diphenylphosphino)ferrocenedichloro palladium(II)dichloromethane complex, (190 mg) and the flask was degassed and flushedwith argon and stirred at 70° C. overnight. After cooling, the mixturewas partitioned between ethyl acetate (100 mL) and sat. NaHCO₃. Theorganic layer was washed with brine, dried over Na₂SO₄ and concentrated.The product was obtained as a yellow oil (3.0 g). The crude was directlyused in subsequent reaction without further purification. LC/MS: [M+1]⁺314.2.

Step 3:2-methyl-3-nitro-6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridine

A solution of2-propyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyridine(2.00 g, 5.1 mmol), 6-bromo-2-methyl-3-nitropyridine (1.70 g, 7.7 mmol)and 2.0 M sodium carbonate (7.6 mL, 15.3 mmol) in dimethyl formamide (14mL) was stirred at room temperature for 5 minutes, thentetrakis(triphenylphosphine) pallladium(0) (120 mg, 0.1 mmol) was thenadded and the flask was degassed and flushed with argon and stirred at110° C. overnight. After cooling, the mixture was partitioned betweenethyl acetate (200 mL) and water. The organic layer was washed withbrine, dried over Na₂SO₄ and concentrated. The residue was purified byflash chromatography (40 g, 0-70% ethyl acetate in hexanes) to affordthe desired product as a brown solid. ¹H-NMR (300 MHz, CDCl₃): δ 8.70(s, 1H), 8.64 (d, J=5.7 Hz, 1H), 8.37 (d, J=8.7 Hz, 1H), 8.28 (s, 1H),7.62 (s, 1H), 7.56-7.53 (m, 2H), 2.95 (s, 3H), 2.88 (t, J=7.8 Hz, 2H),1.89-1.81 (m, 2H), 1.03 (t, J=7.8 Hz, 3H).

Step 4:2-methyl-6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-amine

To a yellow suspension of2-methyl-3-nitro-6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridine(1.25 g, 3.9 mmol) in ethanol (50 mL), was added tin(II) chloride (2.4g, 12.8 mmol), followed by hydrogen chloride (0.13 mL, 3.9 mmol), andthe reaction was heated to 80° C. for 6 hours. After the reaction hadcooled to ambient temperature, it was poured into an ice-cold solutionof 10.0 g potassium hydroxide in 100 mL of water. The basic mixture wasdiluted with 75 mL of ethyl acetate, the layers separated, and theaqueous layer was extracted with ethyl acetate (3×30 mL). The combinedorganics were dried over sodium sulfate and concentrated and purified byflash chromatography to afford the desired product as a yellow solid. ¹HNMR (300 MHz, CDCl₃): δ 8.58 (d, J=5.4 Hz, 1H), 8.48 (s, 1H), 8.12 (s,1H), 7.59 (d, J=1.8 Hz, 1H), 7.49 (dd, J=5.6 and 2.0 Hz, 1H), 7.29 (s,1H), 6.98 (d, J=8.1 Hz, 1H), 3.67 (bs, 2H), 2.85 (t, J=7.7 Hz, 2H),1.87-1.79 (m, 2H), 1.01 (t, J=7.4 Hz, 3H).

Step 5:N-(cyclopropylmethyl)-2-methyl-6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-amine

To a solution of2-methyl-6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-amine(0.07 g, 0.2 mmol) in dichloroethane (5 mL) was addedcyclopropanecarbaldehyde (22 μL, 0.3 mmol), acetic acid (20 μL, 0.4mmol) and sodium triacetoxyborohydride (0.15 g, 0.7 mmol). The reactionwas stirred at room temperature for 4 hours. The mixture was dilutedwith saturated sodium bicarbonate and dichloromethane. The organic layerwas washed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated. The resulting residue was purified by flash chromatography(4 g, 0-50% ethyl acetates in hexanes) to give title compound as ayellow solid (21 mg, 26%). LC/MS: 348.2 [M+1]⁺; ¹H NMR (300 MHz, CDCl₃):δ 8.57 (d, J=5.4 Hz, 1H), 8.47 (s, 1H), 8.11 (s, 1H), 7.59 (s, 1H), 7.49(d, J=5.1 Hz, 1H), 7.32 (d, J=5.1 Hz, 1H), 6.86 (d, J=8.1 Hz, 1H), 3.02(d, J=7.2 Hz, 2H), 2.85 (t, J=7.7 Hz, 2H), 2.49 (s, 3H), 1.87-1.77 (m,2H), 1.19-1.15 (m, 1H), 1.01 (t, J=7.2 Hz, 3H), 0.66-0.60 (m, 2H),0.34-0.29 (m, 2H).

The following compounds were made in a manner similar to that describedfor Example 106.

Example ¹H NMR (CDCl₃, LC/MS No. Structure 300 MHz) [M + 1] 107

δ 8.58 (d, J = 5.4 Hz, 1H), 8.36 (s, 1H), 8.13 (s, 1H), 7.95 (d, J = 2.4Hz, 1H), 7.59 (d, J = 1.8 Hz, 1H), 7.49 (dd, J = 5.7 and 2.1 Hz, 1H),6.77 (d, J = 2 4 Hz, 1H), 3.02 (d, J = 7.2 Hz, 2H), 2.85 (t, J = 7.7 Hz,2H), 2.48 (s, 3H), 1.89-1.77 (m, 2H), 1.16- 1.07 (m, 1H), 1.01 (t, J =7.2 348.2 Hz, 3H), 0.64-0.58 (m, 2H), 0.32-0.27 (m, 2H). 108

δ 8.57 (d, J = 6.0 Hz, 1H), 8.46 (s, 1H), 8.11 (s, 1H), 7.59 (s, 1H),7.51-7.49 (m, 1H), 7.32 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H),3.70-3.63 (m, 1H), 2.84 (t, J = 7.7 Hz, 2H), 2.44 (s, 3H), 336.31.87-1.79 (m, 2H), 1.29 (d, J = 6.3 Hz, 6H), 1.01 (t, J = 7.2 Hz, 3H).109

δ 8.58 (d, J = 5.4 Hz, 1H), 8.35 (s, 1H), 8.13 (s, 1H), 7.92 (d, J = 2.1Hz, 1H), 7.59 (s, 1H), 7.49 (d, J = 3.6 Hz, 1H), 6.76 (s, 1H), 3.71-3.67(m, 1H), 2.85 (t, J = 7.7 Hz, 2H), 2.47 (s, 3H), 1.87-1.76 (m, 2H), 1.27(d, J = 6.6 Hz, 6H), 1.01 (t, J = 7.2 Hz, 3H). 336.2 110

δ 8.57 (d, J = 6.0 Hz, 1H), 8.35 (s, 1H), 8.13 (s, 1H), 7.93 (d, J = 2.4Hz, 1H), 7.59 (s, 1H), 7.49-7.47 (m, 1H), 6.77 (d, J = 2.4 Hz, 1H),3.86- 3.82 (m, 1H), 2.84 (t, J = 7.7 Hz, 2H), 2.47 (s, 3H), 362.32.08-2.04 (m, 2H), 1.86- 1.67 (m, 8H), 1.01 (t, J = 7.2 Hz, 3H). 111

δ 8.57 (d, J = 5.4 Hz, 1H), 8.46 (s, 1H), 8.11 (s, 1H), 7.59 (s, 1H),7.50-7.49 (m, 1H), 7.31 (d, J = 2.4 Hz, 1H), 6.91 (d, J = 8.7 Hz, 1H),3.85-3.81 (m, 1H), 2.84 362.3 (t, J = 7.7 Hz, 2H), 2.43 (s, 3H),2.12-2.07 (m, 2H), 1.87-1.60 (m, 8H), 1.01 (t, J = 7.2 Hz, 3H). 112

δ 8.58 (d, J = 6.0 Hz, 1H), 8.35 (s, 1H), 8.13 (s, 1H), 7.89 (d, J = 2.4Hz, 1H), 7.59 (s, 1H), 7.49 (d, J = 6.0 Hz, 1H), 6.71 (d, J = 2.4 Hz,1H), 3.97-3.92 (m, 1H), 2.85 (t, J = 7.7 Hz, 2H), 2.49- 348.2 2.47 (m,5H), 1.87-1.77 (m, 6H), 1.01 (t, J = 7.2 Hz, 3H). 113

δ 8.57 (d, J = 5.4 Hz, 1H), 8.46 (s, 1H), 8.10 (s, 1H), 7.59 (s, 1H),7.49 (d, J = 5.7 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 6.78 (d, J = 8.1 Hz,1H), 3.97-3.92 (m, 1H), 2.84 348.2 (t, J = 7.7 Hz, 2H), 2.49- 2.45 (m,5H), 1.90-1.79 (m, 6H), 1.01 (t, J = 7.2 Hz, 3H). 114

δ 8.58 (d, J = 5.4 Hz, 1H), 8.35 (s, 1H), 8.13 (s, 1H), 7.95 (d, J = 2.4Hz, 1H), 7.59 (s, 1H), 7.48 (d, J = 5.2 Hz, 1H), 6.79 (d, J = 2.4 Hz,1H), 4.06-4.02 (m, 2H), 3.59- 3.51 (m, 4H), 2.85 (t, J = 7.7 378.2 Hz,2H), 2.48 (s, 3H), 2.10- 2.05 (m, 2H), 1.87-1.79 (m, 2H), 1.52-1.50 (m,1H), 1.01 (t, J = 7.2 Hz, 3H). (CD₃OD) 115

δ 8.57 (d, J = 6.0 Hz, 1H), 8.47 (s, 1H), 8.11 (s, 1H), 7.59 (s, 1H),7.49 (d, J = 4.8 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 9.1 Hz,1H), 4.07-4.03 (m, 2H), 3.60- 378.2 3.50 (m, 4H), 2.85 (t, J = 7.7 Hz,2H), 2.46 (s, 3H), 2.11- 2.06 (m, 2H), 1.87-1.79 (m, 2H), 1.52-1.50 (m,1H), 1.01 (t, J = 7.2 Hz, 3H).

Example 116:N-(5-methyl-6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)methanesulfonamide

A solution of5-methyl-6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-amine(0.08 g, 0.3 mmol) and pyridine (62 μL, 0.8 mmol) in dichloromethane (5mL) was cooled to 0° C. Then, methanesulfonyl chloride (78 μL, 0.9 mmol)was added, and reaction mixture was allowed to warm to room temperatureovernight to give a yellow suspension. The reaction mixture was quenchedwith saturated sodium bicarbonate. The layers were separated, and theaqueous layer was extracted with dichloromethane (2×20 mL). The combinedorganics were dried over Na₂SO₄ and concentrated. The resulting residuewas purified by flash chromatography (4 g, 0-80% ethyl acetates inhexanes) to give the title compound as a yellow solid (54 mg, 57%).LC/MS: [M+1]⁺ 372.2; ¹HNMR (300 MHz, CDCl₃): δ 8.61 (d, J=6.0 Hz, 1H),8.48 (s, 1H), 8.33 (d, J=2.4 Hz, 1H), 8.22 (s, 1H), 7.60 (s, 2H), 7.51(d, J=3.6 Hz, 1H), 6.46 (bs, 1H), 3.09 (s, 3H), 2.86 (t, J=7.5 Hz, 2H),2.59 (s, 3H), 1.87-1.79 (m, 2H), 1.02 (t, J=7.4 Hz, 3H).

Example 117:N-(2-methyl-6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)methanesulfonamide

The title compound was prepared in a manner analogous to that given forExample 116.

LC/MS: [M+1]⁺ 372.2; ¹HNMR (300 MHz, CDCl₃): δ 8.61 (d, J=5.4 Hz, 1H),8.57 (s, 1H), 8.20 (s, 1H), 7.83 (d, J=5.1 Hz, 1H), 7.60 (s, 1H),7.53-7.44 (m, 2H), 6.20 (bs, 1H), 3.07 (s, 3H), 2.87 (t, J=7.5 Hz, 2H),2.62 (s, 3H), 1.88-1.80 (m, 2H), 1.02 (t, J=7.4 Hz, 3H).

Example 118:5-(4-(3-chloro-5-(cyclobutylamino)pyridin-2-yl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one

Step 1:5-(4-(3-chloro-5-nitropyridin-2-yl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one

A micro wave vial was charged with1-propyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyridin-2(1H)-one(0.55 g, 1.7 mmol), 2-bromo-3-chloro-5-nitropyridine (0.4 g, 1.7 mmol),potassium carbonate (0.7 g, 5.0 mmol) and dioxan (8 mL) and water (2 mL)and the flask was degassed and flushed with argon. PdCl₂(dppf) (0.14 g,0.2 mmol) and was added and the reaction flask was again degassed andflushed with argon. The reaction mixture was then heated to 100° C. in amicrowave for 90 minutes. The reaction was cooled to room temperatureand quenched with water and extracted with ethyl acetate (3×50 mL). Thecombined organics were washed with water, brine and dried over MgSO₄.The solvents were evaporated to dryness and the residue purified byflash chromatography (25 g silica gel, 0-70% ethyl acetate in hexanes)to afford the product as yellow solid. LC/MS: [M+1]⁺, 360.2; ¹HNMR (300MHz, CDCl₃): δ 9.31 (d, J=2.4 Hz, 1H), 8.63 (s, 1H), 8.56 (s, 2H), 7.88(d, J=2.4 Hz, 1H), 7.71 (dd, J=9.9 and 3.0 Hz, 1H), 6.72 (d, J=10.2 Hz,1H), 4.00 (t, J=7.5 Hz, 2H), 1.91-1.83 (m, 2H), 1.03 (t, J=6.9 Hz, 3H).

Step 2:5-(4-(5-amino-3-chloropyridin-2-yl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one

A round bottom flask was charged with5-(4-(3-chloro-5-nitropyridin-2-yl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one(0.25 g, 0.7 mmol), ethanol (20 mL) and tin(II) chloride (0.65 g, 3.4mmol) was added and the reaction mixture heated to 85° C. for 45 min.The reaction mixture was cooled and poured into 20 mL of 2M KOH. Thiswas extracted with isopropanol/chloroform (1:3, 3×50 mL). The combinedorganics were washed with brine and dried over MgSO₄. The solvents wereevaporated to give the product as pale yellow solid which was used inthe next reaction without further purification. LC/MS: [M+1]⁺ 330.2;¹HNMR (300 MHz, CDCl₃): 8.29 (s, 1H), 8.02 (d, J=2.4 Hz, 1H), 7.79 (d,J=3.0 Hz, 1H), 7.68 (dd, J=7.2 and 3.0 Hz, 1H), 7.31 (s, 1H), 7.08 (d,J=2.4 Hz, 1H), 6.68 (d, J=9.3 Hz, 1H), 3.96 (t, J=7.8 Hz, 2H), 3.80 (bs,2H), 1.87-1.81 (m, 2H), 1.00 (t, J=6.9 Hz, 3H).

Step 3:5-(4-(3-chloro-5-(cyclobutylamino)pyridin-2-yl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one

A vial was charged with5-(4-(5-amino-3-chloropyridin-2-yl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one(0.07 g, 0.2 mmol), cyclobutanone (0.08 mL, 1.1 mmol) and1,2-dichloroethane (5 mL) and the reaction mixture was stirred for 15m69 and sodium triacetoxyborohydride (0.14 g, 0.6 mmol) was added andthe reaction mixture stirred at room temperature for 48 hours. Thereaction mixture was quenched with water and extracted withdichloromethane (3×25 mL). The combined organics were washed with brineand dried over MgSO₄. The solvents were evaporated to dryness and theresidue purified by reverse phase HPLC to give the product as off-whitesolid (71 mg, 85%). LC/MS: [M+1]⁺ 384.5; ¹H NMR (300 MHz, CDCl₃): δ 8.27(d, J=3.0 Hz, 2H), 7.91 (d, J=2.4 Hz, 1H), 7.80 (d, J=3.0 Hz, 1H), 7.69(dd, J=9.9 and 3.0 Hz, 1H), 6.87 (d, J=2.1 Hz, 1H), 6.68 (d, J=9.9 Hz,1H), 4.05-3.92 (m, 3H), 2.49-2.45 (m, 2H), 1.89-1.82 (i, 6H), 1.01 (t,J=7.4 Hz, 3H).

The following compounds are made in a manner similar to that describedfor Example 118.

Example LC/MS No. Structure ¹H NMR (CDCl₃, 300 MHz) [M + 1] 119

δ 8.28 (d, J = 3.6 Hz, 2H), 7.94 (d, J = 2.4 Hz, 1H), 7.80 (d, J = 2.4Hz, 1H), 7.71 (dd, J = 9.3 and 3.0 Hz, 1H), 6.94 (d, J = 2.4 Hz, 1H),6.68 (d, J = 9.9 Hz, 1H), 3.97 (t, J = 7.4 Hz, 2H), 3.86-3.79 (m, 2H),2.11-2.05 (m, 2H), 1.89-1.68 (m, 6H), 1.53-1.50 (m, 2H), 1.01 (t, J =7.4 Hz, 3H). 398.7 120

δ 8.01 (d, J = 10.5 Hz, 2H), 7.87 (d, J = 3.0 Hz, 1H), 7.80 (d, J = 2.7Hz, 1H), 7.71 (dd, J = 9.9 and 3.0 Hz, 1H), 6.72-6.70 (m, 1H), 6.67 (s,1H), 3.99-3.95 (m, 3H), 2.49-2.45 (m, 2H), 2.45 (s, 3H), 1.89-1.81 (m,6H), 1.01 (t, J = 7.4 Hz, 3H). 364.4 121

δ 8.02 (d, J = 6.9 Hz, 2H), 7.92 (d, J = 2.4 Hz, 1H), 7.80 (d, J = 2.7Hz, 1H), 7.71 (dd, J = 9.9 and 3.0 Hz, 1H), 6.78 (d, J = 2.1 Hz, 1H),6.68 (d, J = 9.6 Hz, 1H), 4.06-3.95 (m, 4H), 3.59- 3.50 (m, 4H), 2.46(s, 3H), 2.09- 2.05 (m, 2H), 1.89-1.81 (m, 2H), 1.58-1.50 (m, 2H), 1.01(t, J = 7.4 Hz, 3H). 394.1 122

δ 8.28 (d, J = 1.8 Hz, 2H), 7.97 (d, J = 2.4 Hz, 1H), 7.80 (d, J = 3.0Hz, 1H), 7.70 (dd, J = 9.9 and 3.0 Hz, 1H), 6.96 (d, J = 2.4 Hz, 1H),6.68 (d, J = 9.3 Hz, 1H), 4.07-3.95 (m, 4H), 3.78- 3.75 (m, 1H),3.58-3.51 (m, 3H), 2.09-2.05 (m, 2H), 1.89- 1.82 (m, 2H), 1.54-1.49 (m,2H), 1.01 (t, J = 7.4 Hz, 3H). 394.5 123

δ 8.01 (d, J = 5.7 Hz, 2H), 7.92 (d, J = 2.4 Hz, 1H), 7.80 (d, J = 2.1Hz, 1H), 7.71 (dd, J = 9.9 and 3.0 Hz, 1H), 6.77 (d, J = 2.1 Hz, 1H),6.68 (d, J = 9.6 Hz, 1H), 3.97 (t, J = 7.4 Hz, 2H), 3.85-3.81 (m, 1H),2.45 (s, 3H), 2.08-2.06 (m, 2H), 1.89-1.67 (m, 4H), 1.56-1.40 (m, 4H),1.01 (t, J = 7.4 Hz, 3H). 378.3 124

δ 8.12 (s, 1H), 8.01-7.97 (m, 2H), 7.78-7.69 (m, 2H), 7.33 (d, J = 5.7Hz, 1H), 6.88-6.85 (m, 1H), 6.68 (d, J = 10.2 Hz, 1H), 3.99-3.94 (m,3H), 1.88-1.81 (m, 6H), 1.63-1.59 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H).350.4 125

δ 8.12 (s, 1H), 8.02 (d, J = 7.2 Hz, 2H), 7.78 (s, 1H), 7.70 (d, J = 9.3Hz, 1H), 7.35 (d, J = 9.0 Hz, 1H), 6.95 (d, J = 7.5 Hz, 1H), 6.68 (d, J= 9.6 Hz, 1H), 4.06-3.94 (m, 4H), 3.58-3.50 (m, 3H), 2.09-2.05 (m, 2H),1.89-1.81 (m, 2H), 1.55-1.50 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H). 380.1126

δ 8.12 (s, 1H), 8.01 (s, 2H), 7.79 (s, 1H), 7.70 (d, J = 9.0 Hz, 1H),7.34 (d, J = 8.1 Hz, 1H), 6.93 (d, J = 6.0 Hz, 1H), 6.68 (d, J = 9.6 Hz,1H), 3.97 (t, J = 7.4 Hz, 2H), 3.85-3.81 (m, 1H), 2.08-2.06 (m, 2H),1.89-1.67 (m, 6H), 1.56-1.40 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H). 364.4127

δ 8.48 (s, 1H), 8.24 (s, 1H), 8.18 (s, 1H), 8.01 (d, J = 9.3 Hz, 1H),7.89 (s, 1H), 6.99 (s, 1H), 6.70 (d, J = 9.9 Hz, 1H), 3.95 (d, J = 7.2Hz, 3H), 2.45 (s, 1H), 1.98- 1.1.86 (m, 4H), 1.39 (s, 1H), 0.64 (d, J =6.9 Hz, 2H), 0.51 (d, J = 3.6 Hz, 2H). (CD3OD) 396.6 128

δ 8.27 (d, J = 4.8 Hz, 2H), 7.91 (d, J = 3.0 Hz, 1H), 7.75-7.69 (m, 2H),6.87 (d, J = 2.7 Hz, 1H), 6.68 (d, J = 9.9 Hz, 1H), 4.05-3.92 (m, 2H),3.82 (d, J = 7.8 Hz, 2H), 2.49-2.45 (m, 2H), 2.29-2.20 (m, 1H),1.90-1.83 (m, 4H), 0.99 (d, J = 6.9 Hz, 6H). 398.5 129

δ 8.28 (d, J = 3.6 Hz, 2H), 7.97 (s, 1H), 7.75-7.69 (m, 2H), 6.96 (s,1H), 6.68 (d, J = 9.3 Hz, 1H), 4.07-4.03 (m, 2H), 3.82 (d, J = 7.8 Hz,2H), 3.75-3.67 (m, 1H), 3.59-351 (m, 4H), 2.25-2.04 (m, 4H), 1.00 (d, J= 6.3 Hz, 6H). 428.6 130

δ 8.48 (s, 1H), 8.25 (d, J = 2.4 Hz, 1H), 8.17 (s, 1H), 8.03-7.98 (m,1H), 7.92 (d, J = 2.4 Hz, 1H), 7.06 (d, J = 2.4 Hz, 1H), 6.69 (d, J =9.3 Hz, 1H), 3.94 (d, J = 7.2 Hz, 2H), 3.82-3.77 (m, 1H), 2.07- 2.01 (m,2H), 1.78-1.67 (m, 4H), 1.57-1.51 (m, 2H), 1.39-1.35 (m, 1H), 0.65-0.59(m, 2H), 0.52- 0.48 (m, 2H). (CD₃OD) 410.5

Additional compounds of the invention (Table A), which can be preparedusing methods disclosed herein and known to one of ordinary skill in theart, include

Biological Example 1 Inhibition Assay

Quantitative PCR (qPCR)

HepG2 cells were grown in Dulbecco's Modified Eagle Medium (DMEM)containing 5% FBS and antibiotic-antimycotic in a humidified incubatorat 37° C. with 5% CO₂. All three components were purchased fromThermoFisher Scientific (Catalog numbers are U.S. Pat. Nos. 11,995,073,26,140,079, and 15240062, respectively). Treatments were done induplicates for each dose of each compound. For control and treated eachtreatment, 400,000 HepG2 cells were seeded onto 1 well of 24-well plate.After one day in culture, cells were treated with the test compound (1μM and/or 10 μM, as indicated below in Table 1) for 24 hours in DMEMwith 5% FBS. Compounds were diluted using DMSO from 20 mM stocks. TotalRNAs were extracted using RNA extraction kit (Cat #: 45001163, FisherScientific) or Trizol. If Trizol was used, RNAs were treated with DNaseI (cat #: 18068015, ThermoFisher Scientific) before qPCR. RNAconcentrations were measured on a Nanodrop. One-step qPCR were performedusing SYBR Green One Step qPCR Kit (Cat #: B25002, Biotool). 10 ng RNAwas used in each 10-ul reaction. Triplicate reactions were done for eachRNA sample. qPCR was performed on an ABI StepOnePlus using the program:Holding stage step 1, 50° C. 3 min, step 2, 95° C. 5 min; Cycling stage(40 cycles) step 1, 95° C. 10 sec, step 2, 60° C. 30 sec. Primersequence was as follows: SCD1,5′-cggtattctggggtgaa-3′/5′-gggggctaatgttcttgtca-3′.

All data was measured in HepG2 cells. % inhibition data of SCD1expression are provided in Table 1. % inhibition at 10 μM is provided asfollows: A≥75%; 75%>B≥50%; 50%>C≥10%. % inhibition at 1 μM is providedas follows: A1≥30%; 30%>B1≥2%. NI means no inhibition in the assay atthe indicated concentration of compound tested. NT means not tested.

Inhibition Percentage (%) Ex. No. 1 μM 10 μM  1 NT A  2 NT A  3 NT A  4NT A  5 NT C  6 NT A  7 NI A  8 NT A  9 A1 A 10 A1 A 11 NT C 12 NT NI 13A1 A 14 A1 A 15 B1 A 16 B1 A 17 A1 A 18 NI A 19 B1 A 20 NT C 21 B1 A 22NT NI 23 B1 A 24 A1 A 25 A1 A 26 A1 A 27 A1 A 28 B1 A 29 B1 A 30 NT B 31NT NI 32 NT A 33 A1 A 52 A1 A 34 B1 B 35 B1 B 36 NI B 53 B1 A 54 NI B 37NI NI 38 A1 A 44 B1 A 45 A1 A 39 B1 C 55 B1 A 40 A1 B 56 B1 A 57 B1 A 47NI C

Biological Example 2 Gene Expression Assay

Quantitative PCR (qPCR)

HepG2 cells were obtained from ATCC and grown in Dulbecco's ModifiedEagle Medium (DMEM) supplemented with 10% FBS in a 5% CO₂ incubator at37° C. For the assay, the cells were plated in 96-well plates at aconcentration of 75,000 cells/well in DMEM with 5% FBS. The compoundswere serially diluted in DMSO from 30 to 0.1 mM, and then diluted 1:1000in growth medium. The medium was added to the cells in duplicate 24 hafter plating. After 24 h of incubation, the RNA was isolated from thecells using the RNAqueous®-96 Total RNA Isolation Kit (Ambion). Theeluted RNA was reverse transcribed using the Cells-to-Ct kit reversetranscriptase (Ambion). For the quantitative PCR, the cDNA was analysedusing the Power SYBR® Green PCR Master Mix (Applied Biosystems) and genespecific primers. The reaction was run on an ABI7300 thermocycler andthe instrument software was used to determine Ct values. The fold changeof mRNA expression relative to the vehicle control was calculated usingthe method by Livak. Primer sequence was as follows: SCD1,5′-cctggtatttctggggtgaa-3′/5′-gggggctaatgttcttgtca-3′. FBS: Hyclone, lot#FRG26939.

All data was measured in HepG2 cells. % inhibition data of SCD1expression are provided in Table 2. % inhibition at 10 μM is provided asfollows: A>75%; 75%>B≥50%; 50%>C>25%; and 25%>D>1%. NI means noinhibition in the assay at the indicated concentration of compoundtested. NT means not tested.

TABLE 2 Inhibition Percentage Ex. No. (%) at 1 μM  59 A 106 D 107 C 108D 109 C 110 B 111 D 112 D 113 D 114 C 115 D  60 B  61 D  62 B  70 D  84A  71 C  72 C  69 A  79 A 116 C  74 C  75 C 117 A  63 A  64 A  65 A  85B  86 A  66 D  82 NI  83 C  67 C  87 A  88 A  89 B  76 B 118 NI 119 B120 C 121 D 122 C 123 B 124 NI 125 NI 126 C  77 A  68 B 127 B 128 B 129B 130 B  90 D  91 A  93 A  92 NI  94 B  95 A  96 A  78 C  97 A  80 B  98B  81 C  99 C 100 A 101 B 102 C 103 C 104 A 105 D

Biological Example 3 Cell Viability Assay

HepG2, Huh7, Hep3B2.1-7, SK-HEP-1, MDA-MB-231, T47D, MCF7, DU145 cellsare cultured in DMEM containing 5% FBS and antibiotic-antimycotic.MOLT4, RPMI8226, and LNCaP cells are cultured in RPMI1640 (Cat #:A1049101, Fisher Scientific) containing 5% FBS andantibiotic-antimycotic. HepaRG cells are cultured in William E medium(Cat #: A1217601, Fisher Scientific) containing 5% FBS, glutaMAX (cat #:35050061, Fisher Scientific), and antibiotic-antimycotic. All cells aregrown in a humidified incubator at 37° C. with 5% CO₂. For the assay,2,000 HepG2, MDA-MB-231, T47D, MCF7, and DU145 cells, 3,000 Huh7,Hep3B2.1-7, and SK-HEP-1 cells and 10,000 cells of MOLT4, RPMI8226, andLNCaP cells are seeded into each well of 96 well plates. After one dayin culture, cells are treated with a test compound (0, 1, 10, 32, 100,320, 1000, 3200, 10000, and 20000 nM) for 48 and 72 hr. The cellviability is assessed using Thiazolyl Blue Tetrazolium Bromide (MTT)assay. 5 mg/mL MTT is added in an amount equal to 10% of the culturemedium volume after 48- and 72-hr treatment with the test compound.After the plates are incubated at 37° C. for 3.5 hours for HepG2, Huh7,Hep3B2.1-7, SK-HEP-1, MDA-MB-231, T47D, MCF7, DU145 HepaRG the medium isremoved and formazan crystals are dissolved in 100 μL. The absorbance ismeasured on a Cytation 5 epi-fluorescence microscope in the BCMIntegrated Microscopy core at wavelengths of 550 nm, and 690 nm. Theabsorbance at 550 nm subtracted by the absorbance at 690 nm is used forgraphing. Curves are plotted using GraphPad Prism program. For MOLT4,RPMI8226, and LNCaP the medium was not removed and equal volume of 10%SDS with 0.01 HCL was added and incubated at 37 C overnight. Theabsorbance at 570 nm subtracted by the absorbance at 690 nm is used forgraphing. Curves are plotted using GraphPad Prism program.

Results

Effect of a test compound on the growth of liver cancer cell lines:Several liver cancer cell lines were tested for growth inhibition by atest compound after 48 and 72 hours treatment. After 48 hours treatment,the test compound inhibited the growth at IC₅₀'s of 0.37, 1.2, 4.4, 6.6and 1.2 μM in liver cell lines HepG2, Huh7, Hep3B2.1-7, SK-HEP-1, andthe terminally-differentiated hepatic stem cells HepaRG, respectively(FIG. 1A). When these cells were treated for 72 hours the IC₅₀'s weresignificantly lower at 0.12, 2.1, 5.4, 1.2, and 0.79 μM respectively(FIG. 1B).

Effect a test compound on the viability of prostate cancer cell lines:Human prostate cancer cells LNCap were cultured in in RPMI1640 with 5%FBS and treated for 48 and 72 hours. The cell viability was determinedusing MTT assay; N=3). Curves were plotted using GraphPad Prism program.IC₅₀'s were determined under conditions described above. The inhibitionof this cell line was dose dependent and IC₅₀ was 0.86 and 0.25 μM after48 and 72 hours, respectively. See FIGS. 2A and 2B.

Effect of a test compound on the viability of Leukemia cells: Leukemiacell lines MOLT4 and RPMI8226 were cultured in RPMI1640 with 5% FBS andtreated with either 0.1% DMSO (control) and different doses for 48 or 72hours of the test compound as described above. The cell viability wasdetermined using MTT assay; N=3). Curves were plotted using GraphPadPrism program. As shown in FIG. 3A cell viability of MOLT4 and RPMI8226Cells was 1.9 and 2.8 μM, respectively after 48 hours treatment. Thecell viability was significantly lower after 72 hour treatment and IC₅₀was 0.43 and 0.62 uM respectively (FIG. 3B).

Biological Example 4 Immunoblotting Assay

For the experiment, 3*10⁵ cells are seeded in 6 well plates cultured incomplete medium with 5% fetal bovine serum at 37° C., 5% CO₂, 95% airand 100% relative humidity for 24 hours, then treated with differentdosage of the test compound (0, 5, 10 or 20 μM) for another 6, 24 or 48h. After treatment, cells are washed once with ice-cold PBS and scrapedinto radioimmunoprecipitation assay (RIPA) lysis buffer, with additionof protease and phosphatase inhibitor cocktail. The extract is sonicated(3*10 sec) and centrifugation at 12,000 rpm for 10 min. The proteinconcentration of each total cell extract is measured by BCA kit (Bio-redprotein assay). Equal amounts of protein extracts are separated ongradient 4% to 12% Bis-Tris SDS-PAGE gel (Bio-red) and then transferredto a PVDF membrane. After blocking for 1 hour in a PBS containing 0.1%Tween 20 and 5% nonfat milk, the membrane is probed with indicatedantibodies, followed by secondary antibodies conjugated to IRDye 800CWand then used ODYSSEY imaging system to detect MVD, SCD1, SREBP1,SREBP2, and/or PCSK9 protein expression.

Biological Example 5 In Vivo Model

Sprague-Dawley rats (100-200 gm) will be obtained from Charles RiverBreeding Laboratories, Wilmington, Mass. Commercial laboratory chow andwater will be provided ad libitum. ob/ob Mice (10 per group) are fednormal chow (control diet) or chow that contains 100 mg/kg, 200 mg/kg,300 mg/kg or 400 mg/kg of the test compound. The test compound isadministered orally to ob/ob mice daily over a period of 8 weeks. Dailyfood intake and water consumption are carefully monitored. Mice areweighed daily, and fat and lean body content are determined bydual-energy X-ray absorptiometry (DEXA). % fat is calculated as fatweight/fat+lean weight. Blood constituents are determined using standardprocedures. Glucose tolerance is measured in order to investigate theability of treated mice to clear blood glucose compared to controlanimals. Three groups (10 per group) of mice are fasted overnight andblood glucose levels are measured at 0, 30, 60, and 120 minutes afterthe injection of glucose (2 g/kg body weight).

Biological Example 6 In Vivo Model

Sprague-Dawley rats have been used to study human obesity induced by aWestern diet (WD) (high-fat, high-carbohydrate diet). Twenty 5- to6-week-old male rats are fed a WD ad libitum for 3 weeks. Foodconsumption and body weight are measured every 3 days. Obesity andweight gain are first seen after 2 weeks and become most apparent after4-5 weeks of this diet. This diet brings about insulin resistance inabout 2 weeks. After 3 weeks of feeding WD, the test compound isadministered daily at 10 mg/kg to the experimental group (20 rats) byoral gavage. The control group (n=20) is given vehicle only at the sametime. Animals are treated for 2 months.

Food intake, water consumption, and body weight are determined andrecorded every 3 days for the duration of the experiment. Rats are fedthe WD diet for a total of 2 months and 3 weeks. The first 3 weeks areWD alone. After the first 3 weeks, the experimental groups receives thetest compound daily.

Before the start of dosing with the test compound, baseline bloodconstituents are determined. The animals are fasted for 8 hours, and TG,HDL, LDL, VLDL, cholesterol, glucose and insulin levels are determinedusing standard methods. A glucose tolerance test (GTT) is carried outusing standard methods. Body composition (lean and body fat) isdetermined using dual-energy X-ray absorptiometry on live animals, usingstandard methods. Body weight and food intake are measured every week,and 1 month after the start of the treatment, blood constituents aredetermined to measure glucose, TG, HDL, LDL and VLDL in addition to theliver enzymes: aspartate aminotransferase (AST) and alanineaminotransferase (ALT). GTT is also performed in order to assess theinsulin-resistant state 4 and 8 weeks after the start of the treatment.Fat and lean body mass are assessed by ¹H magnetic resonancespectroscopy (Bruker BioSpin, Billerica, Mass., USA) before and after 4weeks of treatment. A comprehensive animal metabolic monitoring system(CLAMS: Columbus Instruments, Columbus, Ohio, USA) is used to evaluateactivity, food consumption and energy expenditure before and after 4weeks of treatment. Energy expenditure and food intake data isnormalized with respect to body weight. Energy expenditure andrespiratory quotient (RQ) are calculated from the gas exchange data.Energy expenditure=(3.815+1.232*RQ)*VO₂. RQ is the ratio of VCO₂ to VO₂,which changes depending on the energy source the animal is using. Whencarbohydrates are the only substrate being oxidized, the RQ is 1.0, andit is 0.7 when only fatty acids are oxidized. Activity is measured on anx and z-axis using infrared beams to count the amount of beam breaksduring the specified measurement period. Feeding is measured byrecording the difference in the scale measurement of the Center-Feederfrom one time point to another.]

Following the 2 months of treatment, rats are sacrificed to determinethe biochemical and histopathological impact of the test compound onliver, muscle, heart and adipose tissues. The tissues are collected,weighed and kept at −80° C. for further analyses, as follows:

-   -   Histological staining for lipid, glycogen and general tissue        structure.    -   TG and cholesterol levels using biochemical methods.    -   Assays for lipogenic enzymes, such as fatty acid synthase (FAS),        acetyl-CoA carboxylases (ACC1 and ACC2), stearoyl-CoA desaturase        (SCD1), and enzymes of cholesterol synthesis, 3-hydroxy 3-methyl        glutaryl-CoA synthase and reductase, among others.    -   Expression level of genes previously found to be modulated by        fatostatin in both cell culture and mouse studies, including        SREBP1 and -2, done using real-time PCR for RNA levels and        Western blot assays for protein.

Statistical analyses are performed with commercially available software.Data are expressed as mean±SD. Statistical comparison of changes betweencontrol and treated animals are analyzed by one-way ANOVA. UnpairedStudent 1-test is used to compare the treated animals and the controls.Values of P<0.05 are considered statistically significant.

Biological Example 7 In Vivo Model

Animals: The ob/ob mice were purchased from Jackson's Laboratory whenthey are about 5-6 weeks old males matched and weighed about 28-31 gram.The mice were housed as group of 4-5 mice per cage. After receiving themice, they were housed at animal facility under controlled conditions oftemperature and day and night cycle. After a week period of adapting tothe new facility mice weight were recorded before the experiments startand body composition (fat and lean) were determined by Echo MRI(reference: Galgani J E, Smith S R & Ravussin E (2011) Assessment ofEchoMRI-AH versus dual-energy X-ray absorptiometry to measure human bodycomposition. Int J Obes 35, 1241-1246.

Test compound formulation: Compounds were weighed and mixed with asolution containing 40% (VN) PEG400, 18% solutol, and 42% water. Thetest compound was weighed and freshly prepared prior to each treatmentby mixing the vehicle with the compound followed by a brief sonicationfor 30 seconds and the doses were calculated according to the bodyweight. Two doses, 0.25 and 2.5 mg/kg, in addition to placebo were used.

Food Intake: Food consumptions and body weights were determined at about3 pm daily. Food consumption is measured by weighing the food that isadded daily to the cages minus the food that is left in the cages.

Body weight and composition: Mice-weights were determined daily at 3-4pm and doses delivered and calculated according to the weight. Ob/Obmice weight increases significantly on a daily bases. The well-being ofthe mice was closely monitored, including any obvious health issues suchas morbidity, movement an extreme reduction in food intake etc In orderto determine the effect of the test compound on reducing total body fatbody composition was determined using ECHOMRI method every two weeks.

Blood Constituents: In order to determine blood constituents, mice werefasted for six hours and blood was withdrawn to measure Glucose andother blood constituents such as TG, LDL, HDL, VLDL and Liver enzymeswere performed.

In order to determine the effect of the test compound on reducing totalbody fat body composition was determined using ECHOMRI method every twoweeks.

Results

Food Intake: Food consumptions and body weights were determined at about10 am daily. Food consumptions were measured by weighing the food thatwas added daily to the cages minus the food that was left in the cages.No spillages were noticed in the cages. Food consumption was verysimilar in all groups: 263, 267 and 273 gram/mouse after 11 weeks,suggesting that the test compound at doses of 0 mg/kg, 0.25 mg/kg, and2.5 mg/kg did not affect food intake (appetite).

Fat, lean and body weight after ten weeks of treatment with the testcompound. The initial weights of the mice upon arrival were about 28-30gram, and the mice were divided into 3 groups of five mice in each cage.Mouse weights were determined daily at around 10 am. FIG. 4A shows theincreases in body weights of each experimental group (n=7).Interestingly, the treated groups gained similar weights, at about15-20% less weight than the controls (19.4±0.9, 15.7±1.6 and 16.6±0.9gram/mouse for control, 0.25 and 2.5 mg/kg groups respectively). Therewas no significant change in lean content between the three groups (FIG.4B). When fat content was determined by Echo MRI every 2-3 weeks, thefat amount in both treated groups was similar (FIG. 4C). The fat amountwas consistently lower compared to the controls and after 10 weeks thefat weights were 32.6 0.7, 29.4±1.0 and 30.1±1.1-gram fat/mouse ofcontrol, 0.25 and 2.5 mg doses respectively. These results suggest thatthe decreased in weight gained in the treated groups was mainly due toreduced fat accumulation. In the figures, values are mean±SE (n=7).

Blood analyses after nine weeks of treatment. The effect of the testcompound on blood glucose and serum lipid levels were determined afternine weeks of treatment. Blood was withdrawn from the mousesubmandibular vein after 6 hours fasting conditions. Glucose levels wasdetermined using McKesson blood glucose meter and serum was separatedfor determination of lipids, and liver enzymes Lipids and liver enzymeswere determined by Mouse Metabolism Core (Baylor College of Medicine).As shown in FIG. 5 , the glucose levels in blood of treated 0.25 and 2.5mg/kg groups were 22% and 30% lower than the controls respectively (0.25mg/kg: 130.9±12.2; 2.5 mg/kg: 116.9±10.1, controls: 167.9±15.5 mg/dl).

The triglycerides level decreased about 10 and 17% in serum of 0.25mg/kg and 2.5 mg/kg compared to the controls (73.91±2.37, 67.47±3.50 and81.17±3.81 mg/dl respectively) (FIG. 6A). Total cholesterol was about 10and 15% lower in the 0.25 and 2.5 mg/kg compared to controls(235.03±6.02, 224.77±6.68 and 262.86±9.34 mg/dl respectively) (FIG. 6B).There were no significant differences at the level of HDL between thethree groups (FIG. 6C). However the level of LDL was lower in the bloodof the compound-treated groups which was about 27 and 40% lower for 0.25and 2.5 mg/kg respectively compared to controls (73.6 5.90, 60.14±8.39,and 99.69±3.75 mg/dl respectively) (FIG. 6D). Values are mean±SE.*P<0.05).

Levels of aspartate aminotransferase (AST) and alanine aminotransferase(ALT) in serum of mice were determined after nine weeks of treatment. Asshown in FIGS. 7A and 7B, the level of both enzymes were lower than thecontrol animals, suggesting that the test compound did not cause livertoxicity and may actually improve the liver condition as evident bylower AST and ALT values. AST was about 35% lower in 0.25 and 2.5 mg/kgcompared to control (158±14.92, 157±13.18 and 225±14.60 IU/Lrespectively). ALT was lower by 22% and 35% compared to controls(78±6.63, 65±6.37, and 99±7.15 IU/L respectively). Values are mean±SE.*P<0.05

All publications, patents, and patent applications cited in thisspecification are herein incorporated by reference as if each individualpublication, patent, or patent application were specifically andindividually indicated to be incorporated by reference. While theclaimed subject matter has been described in terms of variousembodiments, the skilled artisan will appreciate that variousmodifications, substitutions, omissions, and changes may be made withoutdeparting from the spirit thereof. Accordingly, it is intended that thescope of the claimed subject matter is limited solely by the scope ofthe following claims, including equivalents thereof.

1. A Compound of Formula (II):

wherein R¹ is phenyl, pyridinonyl, pyridinyl, pyrimidinyl, pyridazinyl,or pyrazinyl; wherein the phenyl, pyridinyl, pyrimidinyl, pyridazinyl,and pyrazinyl rings are substituted with one R^(1a) and additionallyoptionally substituted with a second R^(1a) and additionally optionallysubstituted with a third R^(1a); and wherein the pyridinonyl issubstituted on the nitrogen with R^(1b) and is additionally optionallysubstituted with 1, 2, or 3 R^(1a); each R^(1a) is independently halo,alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, or heterocycloalkylalkyl; R^(1b) is hydrogen, alkyl,alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, orheterocycloalkylalkyl; R²⁰ is

 where 0, 1, or 2 of X¹-X⁴ are nitrogen and the remaining are carbon;each R^(2b) is independently halo, alkyl, haloalkyl, —NO₂, or cyano;R^(2c) is —NO₂ or NH₂; R³ is hydrogen or alkyl; R⁴ is hydrogen or alkyl;R^(5a) and R^(6a) are independently hydrogen or alkyl; and R^(5b) andR^(6b) are independently alkyl; haloalkyl; cycloalkyl; cycloalkylalkyl;heterocycloalkyl; heterocycloalkylalkyl; and wherein each cycloalkyl,either alone or as part of another group, is independently optionallysubstituted with one or two groups independently selected from the groupconsisting of alkyl, halo, and haloalkyl; or a pharmaceuticallyacceptable salt thereof; provided that the compound is not4-(1-(3-methylpyridin-4-yl)-1H-pyrazol-4-yl)aniline:4-(1-(2-methylpyridin-4-yl)-1H-pyrazol-4-yl)aniline; or4-(1-(3-chloropyridin-4-yl)-1H-pyrazol-4-yl)aniline.
 2. The Compound ofclaim 1, wherein R¹ is phenyl, pyridinonyl, or pyridinyl; where thephenyl and pyridinyl are optionally substituted with 1 or 2 R^(1a) andwhere the pyridinonyl is substituted on the nitrogen with R^(1b) and isadditionally optionally substituted with 1 R^(1a); or a pharmaceuticallyacceptable salt thereof.
 3. (canceled)
 4. (canceled)
 5. (canceled) 6.(canceled)
 7. The Compound of claim 1, wherein R³ and R⁴ are bothhydrogen; or a pharmaceutically acceptable salt thereof.
 8. The Compoundof claim 1, wherein R³ and R⁴ are both methyl, R³ is hydrogen and R⁴ ismethyl, or R³ is hydrogen and R⁴ is methyl; or a pharmaceuticallyacceptable salt thereof.
 9. (canceled)
 10. (canceled)
 11. (canceled) 12.(canceled)
 13. (canceled)
 14. (canceled)
 15. (canceled)
 16. The Compoundof claim 1, wherein the R² ring is substituted with a first R^(2b); andwhen the R² ring is phenyl or pyridinyl, R² is additionally optionallysubstituted with a second R^(2b); or a pharmaceutically acceptable saltthereof.
 17. The Compound of claim 1, wherein the first R^(2b) is halo;or a pharmaceutically acceptable salt thereof.
 18. The Compound of claim1, wherein the first R^(2b) is chloro or fluoro; or a pharmaceuticallyacceptable salt thereof.
 19. (canceled)
 20. (canceled)
 21. The Compoundof claim 1, wherein the first R^(2b) is —CH₃; or a pharmaceuticallyacceptable salt thereof.
 22. (canceled)
 23. The Compound of claim 1,wherein R^(2c) is —NO₂; or a pharmaceutically acceptable salt thereof.24. The Compound of claim 1, wherein R^(2c) is —NH₂; or apharmaceutically acceptable salt thereof.
 25. (canceled)
 26. (canceled)27. The Compound of claim 1, wherein R¹ is substituted with one R^(1a);or a pharmaceutically acceptable salt thereof.
 28. The Compound of claim27, wherein R^(1a) is alkyl; or a pharmaceutically acceptable saltthereof.
 29. The Compound of claim 1, wherein R^(1b) is alkyl, alkenyl,haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, orheterocycloalkylalkyl; or a pharmaceutically acceptable salt thereof.30. The Compound of claim 1, wherein R^(1b) is alkyl, haloalkyl,cycloalkylalkyl, or heterocycloalkylalkyl where theheterocycloalkylalkyl is optionally substituted with an alkyl group on aring nitrogen of the heterocycloalkyl ring; or a pharmaceuticallyacceptable salt thereof.
 31. The compound of claim 1, wherein thecompound is selected from the following compounds:4-(4-(4-nitrophenyl)-1H-pyrazol-1-yl)-2-propylpyridine,4-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)aniline,5-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine,4-(4-(2-chloro-4-nitrophenyl)-1H-pyrazol-1-yl)-2-propylpyridine,3-chloro-4-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)aniline,6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-amine,4-(4-(5-nitropyridin-2-yl)-1H-pyrazol-1-yl)-2-propylpyridine,3-chloro-5-nitro-2-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridine,5-chloro-6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-amine,5-(3,5-dimethyl-1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine,5-(4-(6-aminopyridin-3-yl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one,5-(4-(4-nitrophenyl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one,5-(4-(4-aminophenyl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one,5-(3-methyl-1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine,5-(4-(2-chloro-4-nitrophenyl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one,5-(4-(4-amino-2-chlorophenyl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one,5-(4-(4-amino-2-fluorophenyl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one,5-amino-2-(1-(6-oxo-1-propyl-1,6-dihydropyridin-3-yl)-1H-pyrazol-4-yl)benzonitrile,5-(4-(4-nitro-2-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one,5-(4-(4-amino-2-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one,5-(4-(2-chloro-4-nitrophenyl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one,5-(4-(4-amino-2-chlorophenyl)-1H-pyrazol-1-yl)-1-propylpyridin-2(1H)-one,2-methyl-3-nitro-6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridine,2-methyl-6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-amine,and5-methyl-6-(1-(2-propylpyridin-4-yl)-1H-pyrazol-4-yl)pyridin-3-amine; ora pharmaceutically acceptable salt thereof.
 32. A pharmaceuticalcomposition comprising a Compound of claim 1 or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier.
 33. Amethod of treating a condition, disease, or disorder associated withabnormal activation of the SREBP pathway comprising administering to apatient in need thereof a therapeutically effective amount of theCompound of claim
 1. 34. The method of claim 33 wherein the condition,disease, or disorder is selected from metabolic syndrome, hypertension,type 2 diabetes, dyslipidemia, obesity, pancreatic B-cell dysfunction,atherosclerosis, a cell proliferative disease, reducing body weight, ametabolic disease, hyperlipidemia, a lipoprotein related disease,combined hyoerlipidemia (elevated cholesterol and triglycerides),Frederickson Type IIb, familial combined hyperlipidemia (inherited formof combined hyperlipidemia), familial hypertriglyceridemia, FredericksonType IV, hyperlipoproteinemia Type V, mixed hyperlipidemia, Aquiredhyperlipidemia, Fatty Liver Disease, Nonalcoholic Steatohepatitis,Neutral Lipid Storage Diseases, Chanarin-Dorfman Syndrome, TissueInflammation such as Cutaneous Psoriasis (associated with Metabolicsyndrome), coronary artery disease (atherosclerosis), Post MyocardialInfarction management, Peripheral vascular disease, cerebrovasculardisease—thrombotic, Type II Diabetes Mellitus, Diabetic Nephropathy,cancer, Hepatocellular Carcinoma, Glioblastoma Multiforme, ProstateCancer, Post menopausal Breast Carcinoma, Pancreatic Adenocarcinoma,Ovarian cancer, B cell lymphoma, lung cancer, digestive andgastrointestinal cancer, gastrointestinal stromal tumor,gastrointestinal carcinoid tumor, colon cancer, rectal cancer, analcancer, bile duct cancer, small intestine cancer, stomach (gastric)cancer, esophageal cancer, gall bladder cancer, appendix cancer, renalcancer, cancer of the central nervous system, skin cancer, a lymphoma,choriocarcinoma, head and neck cancer, osteogenic sarcoma, and a bloodcancer; or wherein the patient is in need of increased thermogenesis orin need of reducing body weight.
 35. The method of claim 33 wherein thecondition, disease, or disorder is selected from metabolic syndrome,hypertension, type 2 diabetes, dyslipidemia, obesity, pancreatic B-celldysfunction, atherosclerosis, Hepatocellular Carcinoma, GlioblastomaMultiforme, Prostate Cancer, post-menopausal Breast Carcinoma,Pancreatic Adenocarcinoma, Ovarian cancer, B cell lymphoma, lung cancer,digestive and gastrointestinal cancer, gastrointestinal stromal tumor,gastrointestinal carcinoid tumor, colon cancer, rectal cancer, analcancer, bile duct cancer, small intestine cancer, stomach (gastric)cancer, esophageal cancer, gall bladder cancer, appendix cancer, renalcancer, cancer of the central nervous system, skin cancer, a lymphoma,choriocarcinoma, head and neck cancer, osteogenic sarcoma, and a bloodcancer; or wherein the patient is in need of increased thermogenesis orin need of reducing body weight.
 36. The compound of claim 1, of theformula:

or a pharmaceutically acceptable salt thereof.
 37. The compound of claim38, of the formula:

or a pharmaceutically acceptable salt thereof.
 38. The compound of claim38, of the formula:

or a pharmaceutically acceptable salt thereof.
 39. The compound of claim38, of the formula:

or a pharmaceutically acceptable salt thereof.
 40. The compound of claim38, of the formula:

or a pharmaceutically acceptable salt thereof.